FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair
Identifieur interne : 000E88 ( Ncbi/Merge ); précédent : 000E87; suivant : 000E89FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair
Auteurs : Weibin Zhou [États-Unis] ; Edgar A. Otto [États-Unis] ; Andrew Cluckey [États-Unis] ; Rannar Airik [États-Unis] ; Toby W. Hurd [États-Unis] ; Moumita Chaki [États-Unis] ; Katrina Diaz [États-Unis] ; Francis P. Lach [États-Unis] ; Geoffrey R. Bennett [États-Unis] ; Heon Y. Gee [États-Unis] ; Amiya K. Ghosh [États-Unis] ; Sivakumar Natarajan [États-Unis] ; Supawat Thongthip [États-Unis] ; Uma Veturi [États-Unis] ; Susan J. Allen [États-Unis] ; Sabine Janssen [États-Unis] ; Gokul Ramaswami [États-Unis] ; Joanne Dixon [Nouvelle-Zélande] ; Felix Burkhalter [Suisse] ; Martin Spoendlin [Suisse] ; Holger Moch [Suisse] ; Michael J. Mihatsch [Suisse] ; Jerome Verine [France] ; Richard Reade [France] ; Hany Soliman [France] ; Michel Godin [France] ; Denes Kiss [Suisse] ; Guido Monga [Italie] ; Gianna Mazzucco [Italie] ; Kerstin Amann [Allemagne] ; Ferruh Artunc [Allemagne] ; Ronald C. Newland [Australie] ; Thorsten Wiech [Allemagne] ; Stefan Zschiedrich [Allemagne] ; Tobias B. Huber [Allemagne] ; Andreas Friedl ; Gisela G. Slaats [Pays-Bas] ; Jaap A. Joles [Pays-Bas] ; Roel Goldschmeding [Pays-Bas] ; Joseph Washburn [États-Unis] ; Rachel H. Giles [Pays-Bas] ; Shawn Levy [États-Unis] ; Agata Smogorzewska [États-Unis] ; Friedhelm Hildebrandt [États-Unis]Source :
- Nature genetics [ 1061-4036 ] ; 2012.
Abstract
Chronic kidney disease (CKD) represents a major health burden
Url:
DOI: 10.1038/ng.2347
PubMed: 22772369
PubMed Central: 3412140
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Lach</name><affiliation wicri:level="2"><nlm:aff id="A2">Laboratory of Genome Maintenance, The Rockefeller University, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Genome Maintenance, The Rockefeller University, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Bennett, Geoffrey R" sort="Bennett, Geoffrey R" uniqKey="Bennett G" first="Geoffrey R." last="Bennett">Geoffrey R. 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Ghosh</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Natarajan, Sivakumar" sort="Natarajan, Sivakumar" uniqKey="Natarajan S" first="Sivakumar" last="Natarajan">Sivakumar Natarajan</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Thongthip, Supawat" sort="Thongthip, Supawat" uniqKey="Thongthip S" first="Supawat" last="Thongthip">Supawat Thongthip</name><affiliation wicri:level="2"><nlm:aff id="A2">Laboratory of Genome Maintenance, The Rockefeller University, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Genome Maintenance, The Rockefeller University, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Veturi, Uma" sort="Veturi, Uma" uniqKey="Veturi U" first="Uma" last="Veturi">Uma Veturi</name><affiliation wicri:level="2"><nlm:aff id="A2">Laboratory of Genome Maintenance, The Rockefeller University, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Genome Maintenance, The Rockefeller University, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Allen, Susan J" sort="Allen, Susan J" uniqKey="Allen S" first="Susan J." last="Allen">Susan J. Allen</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Janssen, Sabine" sort="Janssen, Sabine" uniqKey="Janssen S" first="Sabine" last="Janssen">Sabine Janssen</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Ramaswami, Gokul" sort="Ramaswami, Gokul" uniqKey="Ramaswami G" first="Gokul" last="Ramaswami">Gokul Ramaswami</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Dixon, Joanne" sort="Dixon, Joanne" uniqKey="Dixon J" first="Joanne" last="Dixon">Joanne Dixon</name><affiliation wicri:level="1"><nlm:aff id="A3">Central & Southern Regional Genetic Service, Wellington Hospital, Wellington South, New Zealand</nlm:aff><country xml:lang="fr">Nouvelle-Zélande</country><wicri:regionArea>Central & Southern Regional Genetic Service, Wellington Hospital, Wellington South</wicri:regionArea><wicri:noRegion>Wellington South</wicri:noRegion></affiliation></author><author><name sortKey="Burkhalter, Felix" sort="Burkhalter, Felix" uniqKey="Burkhalter F" first="Felix" last="Burkhalter">Felix Burkhalter</name><affiliation wicri:level="1"><nlm:aff id="A4">Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Transplantation Immunology and Nephrology, University Hospital Basel, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Spoendlin, Martin" sort="Spoendlin, Martin" uniqKey="Spoendlin M" first="Martin" last="Spoendlin">Martin Spoendlin</name><affiliation wicri:level="1"><nlm:aff id="A5">Merian Iselin Klinik, CH-4054, Basel, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Merian Iselin Klinik, CH-4054, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Moch, Holger" sort="Moch, Holger" uniqKey="Moch H" first="Holger" last="Moch">Holger Moch</name><affiliation wicri:level="1"><nlm:aff id="A6">Department of Pathology, University Hospital Zurich, Zurich, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Pathology, University Hospital Zurich, Zurich</wicri:regionArea><wicri:noRegion>Zurich</wicri:noRegion></affiliation></author><author><name sortKey="Mihatsch, Michael J" sort="Mihatsch, Michael J" uniqKey="Mihatsch M" first="Michael J." last="Mihatsch">Michael J. Mihatsch</name><affiliation wicri:level="1"><nlm:aff id="A7">Pathology, University Hospital Basel, Basel, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Pathology, University Hospital Basel, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Verine, Jerome" sort="Verine, Jerome" uniqKey="Verine J" first="Jerome" last="Verine">Jerome Verine</name><affiliation wicri:level="1"><nlm:aff id="A8">Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 728, F-75010 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 728, F-75010 Paris</wicri:regionArea><wicri:noRegion>75010 Paris</wicri:noRegion><wicri:noRegion>75010 Paris</wicri:noRegion></affiliation></author><author><name sortKey="Reade, Richard" sort="Reade, Richard" uniqKey="Reade R" first="Richard" last="Reade">Richard Reade</name><affiliation wicri:level="1"><nlm:aff id="A9">Clinique Néphrologique du Pont Allant, Maubeuge, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Clinique Néphrologique du Pont Allant, Maubeuge</wicri:regionArea><wicri:noRegion>Maubeuge</wicri:noRegion><wicri:noRegion>Maubeuge</wicri:noRegion></affiliation></author><author><name sortKey="Soliman, Hany" sort="Soliman, Hany" uniqKey="Soliman H" first="Hany" last="Soliman">Hany Soliman</name><affiliation wicri:level="1"><nlm:aff id="A10">Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Louis, Service de Biochimie, Paris, 75010, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Louis, Service de Biochimie, Paris, 75010</wicri:regionArea><wicri:noRegion>75010</wicri:noRegion><wicri:noRegion>75010</wicri:noRegion></affiliation></author><author><name sortKey="Godin, Michel" sort="Godin, Michel" uniqKey="Godin M" first="Michel" last="Godin">Michel Godin</name><affiliation wicri:level="3"><nlm:aff id="A11">Department of Nephrology and Hemodialysis, Rouen University Hospital, Rouen, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Department of Nephrology and Hemodialysis, Rouen University Hospital, Rouen</wicri:regionArea><placeName><region type="region">Région Normandie</region><region type="old region">Haute-Normandie</region><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Kiss, Denes" sort="Kiss, Denes" uniqKey="Kiss D" first="Denes" last="Kiss">Denes Kiss</name><affiliation wicri:level="1"><nlm:aff id="A12">Renal Division, Kantonsspital Liestal, Liestal, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Renal Division, Kantonsspital Liestal, Liestal</wicri:regionArea><wicri:noRegion>Liestal</wicri:noRegion></affiliation></author><author><name sortKey="Monga, Guido" sort="Monga, Guido" uniqKey="Monga G" first="Guido" last="Monga">Guido Monga</name><affiliation wicri:level="1"><nlm:aff id="A13">Department of Medical Sciences, Faculty of Medicine, University Amedeo Avogadro of the Eastern Piedmont, Novara, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Medical Sciences, Faculty of Medicine, University Amedeo Avogadro of the Eastern Piedmont, Novara</wicri:regionArea><wicri:noRegion>Novara</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A14">Department of Pathology, Maggiore della Carità Hospital, Novara, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pathology, Maggiore della Carità Hospital, Novara</wicri:regionArea><wicri:noRegion>Novara</wicri:noRegion></affiliation></author><author><name sortKey="Mazzucco, Gianna" sort="Mazzucco, Gianna" uniqKey="Mazzucco G" first="Gianna" last="Mazzucco">Gianna Mazzucco</name><affiliation wicri:level="1"><nlm:aff id="A15">Department of Biomedical Sciences and Human Oncology, Faculty of Medicine, University of Torino, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Biomedical Sciences and Human Oncology, Faculty of Medicine, University of Torino</wicri:regionArea><wicri:noRegion>University of Torino</wicri:noRegion></affiliation></author><author><name sortKey="Amann, Kerstin" sort="Amann, Kerstin" uniqKey="Amann K" first="Kerstin" last="Amann">Kerstin Amann</name><affiliation wicri:level="1"><nlm:aff id="A16">Nephropathology, Department of Pathology, University of Erlangen-Nürnberg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Nephropathology, Department of Pathology, University of Erlangen-Nürnberg</wicri:regionArea><wicri:noRegion>University of Erlangen-Nürnberg</wicri:noRegion><wicri:noRegion>University of Erlangen-Nürnberg</wicri:noRegion><wicri:noRegion>University of Erlangen-Nürnberg</wicri:noRegion></affiliation></author><author><name sortKey="Artunc, Ferruh" sort="Artunc, Ferruh" uniqKey="Artunc F" first="Ferruh" last="Artunc">Ferruh Artunc</name><affiliation wicri:level="1"><nlm:aff id="A17">Department of Internal Medicine, Division of Nephrology, University Hospital Tübingen, D-72076 Tübingen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Internal Medicine, Division of Nephrology, University Hospital Tübingen, D-72076 Tübingen</wicri:regionArea><wicri:noRegion>72076 Tübingen</wicri:noRegion><wicri:noRegion>72076 Tübingen</wicri:noRegion><wicri:noRegion>D-72076 Tübingen</wicri:noRegion></affiliation></author><author><name sortKey="Newland, Ronald C" sort="Newland, Ronald C" uniqKey="Newland R" first="Ronald C." last="Newland">Ronald C. Newland</name><affiliation wicri:level="1"><nlm:aff id="A18">Department of Anatomical Pathology, Concord Hospital, Sydney, NSW, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Anatomical Pathology, Concord Hospital, Sydney, NSW</wicri:regionArea><wicri:noRegion>NSW</wicri:noRegion></affiliation></author><author><name sortKey="Wiech, Thorsten" sort="Wiech, Thorsten" uniqKey="Wiech T" first="Thorsten" last="Wiech">Thorsten Wiech</name><affiliation wicri:level="3"><nlm:aff id="A19">Institute of Pathology, University Hospital Freiburg, Freiburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, University Hospital Freiburg, Freiburg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Fribourg-en-Brisgau</region><settlement type="city">Fribourg-en-Brisgau</settlement></placeName></affiliation></author><author><name sortKey="Zschiedrich, Stefan" sort="Zschiedrich, Stefan" uniqKey="Zschiedrich S" first="Stefan" last="Zschiedrich">Stefan Zschiedrich</name><affiliation wicri:level="3"><nlm:aff id="A20">Renal Division, University Hospital Freiburg, Freiburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Renal Division, University Hospital Freiburg, Freiburg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Fribourg-en-Brisgau</region><settlement type="city">Fribourg-en-Brisgau</settlement></placeName></affiliation></author><author><name sortKey="Huber, Tobias B" sort="Huber, Tobias B" uniqKey="Huber T" first="Tobias B." last="Huber">Tobias B. Huber</name><affiliation wicri:level="3"><nlm:aff id="A20">Renal Division, University Hospital Freiburg, Freiburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Renal Division, University Hospital Freiburg, Freiburg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Fribourg-en-Brisgau</region><settlement type="city">Fribourg-en-Brisgau</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A21">BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg</wicri:regionArea><wicri:noRegion>Albert-Ludwigs-University Freiburg</wicri:noRegion><wicri:noRegion>Albert-Ludwigs-University Freiburg</wicri:noRegion><wicri:noRegion>Albert-Ludwigs-University Freiburg</wicri:noRegion></affiliation></author><author><name sortKey="Friedl, Andreas" sort="Friedl, Andreas" uniqKey="Friedl A" first="Andreas" last="Friedl">Andreas Friedl</name><affiliation><nlm:aff id="A22">Department of Pathology and Laboratory Medicine University of Wisconsin, Madison, Wisconsin USA</nlm:aff><wicri:noCountry code="subfield">Wisconsin USA</wicri:noCountry></affiliation></author><author><name sortKey="Slaats, Gisela G" sort="Slaats, Gisela G" uniqKey="Slaats G" first="Gisela G." last="Slaats">Gisela G. Slaats</name><affiliation wicri:level="3"><nlm:aff id="A23">Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Nephrology and Hypertension, University Medical Center, Utrecht</wicri:regionArea><placeName><settlement type="city">Utrecht</settlement><region nuts="2" type="province">Utrecht (province)</region></placeName></affiliation></author><author><name sortKey="Joles, Jaap A" sort="Joles, Jaap A" uniqKey="Joles J" first="Jaap A." last="Joles">Jaap A. Joles</name><affiliation wicri:level="3"><nlm:aff id="A23">Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Nephrology and Hypertension, University Medical Center, Utrecht</wicri:regionArea><placeName><settlement type="city">Utrecht</settlement><region nuts="2" type="province">Utrecht (province)</region></placeName></affiliation></author><author><name sortKey="Goldschmeding, Roel" sort="Goldschmeding, Roel" uniqKey="Goldschmeding R" first="Roel" last="Goldschmeding">Roel Goldschmeding</name><affiliation wicri:level="1"><nlm:aff id="A24">Department of Pathology, University Medical Center Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pathology, University Medical Center Utrecht</wicri:regionArea><wicri:noRegion>University Medical Center Utrecht</wicri:noRegion></affiliation></author><author><name sortKey="Washburn, Joseph" sort="Washburn, Joseph" uniqKey="Washburn J" first="Joseph" last="Washburn">Joseph Washburn</name><affiliation wicri:level="2"><nlm:aff id="A25">University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan</wicri:regionArea><placeName><region type="state">Michigan</region></placeName></affiliation></author><author><name sortKey="Giles, Rachel H" sort="Giles, Rachel H" uniqKey="Giles R" first="Rachel H." last="Giles">Rachel H. Giles</name><affiliation wicri:level="3"><nlm:aff id="A23">Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Nephrology and Hypertension, University Medical Center, Utrecht</wicri:regionArea><placeName><settlement type="city">Utrecht</settlement><region nuts="2" type="province">Utrecht (province)</region></placeName></affiliation></author><author><name sortKey="Levy, Shawn" sort="Levy, Shawn" uniqKey="Levy S" first="Shawn" last="Levy">Shawn Levy</name><affiliation wicri:level="1"><nlm:aff id="A26">HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35806, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35806</wicri:regionArea><wicri:noRegion>Alabama 35806</wicri:noRegion></affiliation></author><author><name sortKey="Smogorzewska, Agata" sort="Smogorzewska, Agata" uniqKey="Smogorzewska A" first="Agata" last="Smogorzewska">Agata Smogorzewska</name><affiliation wicri:level="2"><nlm:aff id="A2">Laboratory of Genome Maintenance, The Rockefeller University, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Genome Maintenance, The Rockefeller University, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Hildebrandt, Friedhelm" sort="Hildebrandt, Friedhelm" uniqKey="Hildebrandt F" first="Friedhelm" last="Hildebrandt">Friedhelm Hildebrandt</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A27">Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:aff id="A28">Howard Hughes Medical Institute, Chevy Chase, MD, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Howard Hughes Medical Institute, Chevy Chase, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22772369</idno><idno type="pmc">3412140</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412140</idno><idno type="RBID">PMC:3412140</idno><idno type="doi">10.1038/ng.2347</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">002E15</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002E15</idno><idno type="wicri:Area/Pmc/Curation">002C65</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">002C65</idno><idno type="wicri:Area/Pmc/Checkpoint">002108</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">002108</idno><idno type="wicri:Area/Ncbi/Merge">000E88</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>FAN1</italic> mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair</title><author><name sortKey="Zhou, Weibin" sort="Zhou, Weibin" uniqKey="Zhou W" first="Weibin" last="Zhou">Weibin Zhou</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Otto, Edgar A" sort="Otto, Edgar A" uniqKey="Otto E" first="Edgar A." last="Otto">Edgar A. Otto</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Cluckey, Andrew" sort="Cluckey, Andrew" uniqKey="Cluckey A" first="Andrew" last="Cluckey">Andrew Cluckey</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Airik, Rannar" sort="Airik, Rannar" uniqKey="Airik R" first="Rannar" last="Airik">Rannar Airik</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Hurd, Toby W" sort="Hurd, Toby W" uniqKey="Hurd T" first="Toby W." last="Hurd">Toby W. Hurd</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Chaki, Moumita" sort="Chaki, Moumita" uniqKey="Chaki M" first="Moumita" last="Chaki">Moumita Chaki</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Diaz, Katrina" sort="Diaz, Katrina" uniqKey="Diaz K" first="Katrina" last="Diaz">Katrina Diaz</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Lach, Francis P" sort="Lach, Francis P" uniqKey="Lach F" first="Francis P." last="Lach">Francis P. Lach</name><affiliation wicri:level="2"><nlm:aff id="A2">Laboratory of Genome Maintenance, The Rockefeller University, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Genome Maintenance, The Rockefeller University, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Bennett, Geoffrey R" sort="Bennett, Geoffrey R" uniqKey="Bennett G" first="Geoffrey R." last="Bennett">Geoffrey R. Bennett</name><affiliation wicri:level="2"><nlm:aff id="A2">Laboratory of Genome Maintenance, The Rockefeller University, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Genome Maintenance, The Rockefeller University, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Gee, Heon Y" sort="Gee, Heon Y" uniqKey="Gee H" first="Heon Y." last="Gee">Heon Y. Gee</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Ghosh, Amiya K" sort="Ghosh, Amiya K" uniqKey="Ghosh A" first="Amiya K." last="Ghosh">Amiya K. Ghosh</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Natarajan, Sivakumar" sort="Natarajan, Sivakumar" uniqKey="Natarajan S" first="Sivakumar" last="Natarajan">Sivakumar Natarajan</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Thongthip, Supawat" sort="Thongthip, Supawat" uniqKey="Thongthip S" first="Supawat" last="Thongthip">Supawat Thongthip</name><affiliation wicri:level="2"><nlm:aff id="A2">Laboratory of Genome Maintenance, The Rockefeller University, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Genome Maintenance, The Rockefeller University, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Veturi, Uma" sort="Veturi, Uma" uniqKey="Veturi U" first="Uma" last="Veturi">Uma Veturi</name><affiliation wicri:level="2"><nlm:aff id="A2">Laboratory of Genome Maintenance, The Rockefeller University, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Genome Maintenance, The Rockefeller University, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Allen, Susan J" sort="Allen, Susan J" uniqKey="Allen S" first="Susan J." last="Allen">Susan J. Allen</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Janssen, Sabine" sort="Janssen, Sabine" uniqKey="Janssen S" first="Sabine" last="Janssen">Sabine Janssen</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Ramaswami, Gokul" sort="Ramaswami, Gokul" uniqKey="Ramaswami G" first="Gokul" last="Ramaswami">Gokul Ramaswami</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Dixon, Joanne" sort="Dixon, Joanne" uniqKey="Dixon J" first="Joanne" last="Dixon">Joanne Dixon</name><affiliation wicri:level="1"><nlm:aff id="A3">Central & Southern Regional Genetic Service, Wellington Hospital, Wellington South, New Zealand</nlm:aff><country xml:lang="fr">Nouvelle-Zélande</country><wicri:regionArea>Central & Southern Regional Genetic Service, Wellington Hospital, Wellington South</wicri:regionArea><wicri:noRegion>Wellington South</wicri:noRegion></affiliation></author><author><name sortKey="Burkhalter, Felix" sort="Burkhalter, Felix" uniqKey="Burkhalter F" first="Felix" last="Burkhalter">Felix Burkhalter</name><affiliation wicri:level="1"><nlm:aff id="A4">Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Transplantation Immunology and Nephrology, University Hospital Basel, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Spoendlin, Martin" sort="Spoendlin, Martin" uniqKey="Spoendlin M" first="Martin" last="Spoendlin">Martin Spoendlin</name><affiliation wicri:level="1"><nlm:aff id="A5">Merian Iselin Klinik, CH-4054, Basel, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Merian Iselin Klinik, CH-4054, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Moch, Holger" sort="Moch, Holger" uniqKey="Moch H" first="Holger" last="Moch">Holger Moch</name><affiliation wicri:level="1"><nlm:aff id="A6">Department of Pathology, University Hospital Zurich, Zurich, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Pathology, University Hospital Zurich, Zurich</wicri:regionArea><wicri:noRegion>Zurich</wicri:noRegion></affiliation></author><author><name sortKey="Mihatsch, Michael J" sort="Mihatsch, Michael J" uniqKey="Mihatsch M" first="Michael J." last="Mihatsch">Michael J. Mihatsch</name><affiliation wicri:level="1"><nlm:aff id="A7">Pathology, University Hospital Basel, Basel, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Pathology, University Hospital Basel, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Verine, Jerome" sort="Verine, Jerome" uniqKey="Verine J" first="Jerome" last="Verine">Jerome Verine</name><affiliation wicri:level="1"><nlm:aff id="A8">Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 728, F-75010 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 728, F-75010 Paris</wicri:regionArea><wicri:noRegion>75010 Paris</wicri:noRegion><wicri:noRegion>75010 Paris</wicri:noRegion></affiliation></author><author><name sortKey="Reade, Richard" sort="Reade, Richard" uniqKey="Reade R" first="Richard" last="Reade">Richard Reade</name><affiliation wicri:level="1"><nlm:aff id="A9">Clinique Néphrologique du Pont Allant, Maubeuge, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Clinique Néphrologique du Pont Allant, Maubeuge</wicri:regionArea><wicri:noRegion>Maubeuge</wicri:noRegion><wicri:noRegion>Maubeuge</wicri:noRegion></affiliation></author><author><name sortKey="Soliman, Hany" sort="Soliman, Hany" uniqKey="Soliman H" first="Hany" last="Soliman">Hany Soliman</name><affiliation wicri:level="1"><nlm:aff id="A10">Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Louis, Service de Biochimie, Paris, 75010, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Louis, Service de Biochimie, Paris, 75010</wicri:regionArea><wicri:noRegion>75010</wicri:noRegion><wicri:noRegion>75010</wicri:noRegion></affiliation></author><author><name sortKey="Godin, Michel" sort="Godin, Michel" uniqKey="Godin M" first="Michel" last="Godin">Michel Godin</name><affiliation wicri:level="3"><nlm:aff id="A11">Department of Nephrology and Hemodialysis, Rouen University Hospital, Rouen, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Department of Nephrology and Hemodialysis, Rouen University Hospital, Rouen</wicri:regionArea><placeName><region type="region">Région Normandie</region><region type="old region">Haute-Normandie</region><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Kiss, Denes" sort="Kiss, Denes" uniqKey="Kiss D" first="Denes" last="Kiss">Denes Kiss</name><affiliation wicri:level="1"><nlm:aff id="A12">Renal Division, Kantonsspital Liestal, Liestal, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Renal Division, Kantonsspital Liestal, Liestal</wicri:regionArea><wicri:noRegion>Liestal</wicri:noRegion></affiliation></author><author><name sortKey="Monga, Guido" sort="Monga, Guido" uniqKey="Monga G" first="Guido" last="Monga">Guido Monga</name><affiliation wicri:level="1"><nlm:aff id="A13">Department of Medical Sciences, Faculty of Medicine, University Amedeo Avogadro of the Eastern Piedmont, Novara, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Medical Sciences, Faculty of Medicine, University Amedeo Avogadro of the Eastern Piedmont, Novara</wicri:regionArea><wicri:noRegion>Novara</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A14">Department of Pathology, Maggiore della Carità Hospital, Novara, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pathology, Maggiore della Carità Hospital, Novara</wicri:regionArea><wicri:noRegion>Novara</wicri:noRegion></affiliation></author><author><name sortKey="Mazzucco, Gianna" sort="Mazzucco, Gianna" uniqKey="Mazzucco G" first="Gianna" last="Mazzucco">Gianna Mazzucco</name><affiliation wicri:level="1"><nlm:aff id="A15">Department of Biomedical Sciences and Human Oncology, Faculty of Medicine, University of Torino, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Biomedical Sciences and Human Oncology, Faculty of Medicine, University of Torino</wicri:regionArea><wicri:noRegion>University of Torino</wicri:noRegion></affiliation></author><author><name sortKey="Amann, Kerstin" sort="Amann, Kerstin" uniqKey="Amann K" first="Kerstin" last="Amann">Kerstin Amann</name><affiliation wicri:level="1"><nlm:aff id="A16">Nephropathology, Department of Pathology, University of Erlangen-Nürnberg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Nephropathology, Department of Pathology, University of Erlangen-Nürnberg</wicri:regionArea><wicri:noRegion>University of Erlangen-Nürnberg</wicri:noRegion><wicri:noRegion>University of Erlangen-Nürnberg</wicri:noRegion><wicri:noRegion>University of Erlangen-Nürnberg</wicri:noRegion></affiliation></author><author><name sortKey="Artunc, Ferruh" sort="Artunc, Ferruh" uniqKey="Artunc F" first="Ferruh" last="Artunc">Ferruh Artunc</name><affiliation wicri:level="1"><nlm:aff id="A17">Department of Internal Medicine, Division of Nephrology, University Hospital Tübingen, D-72076 Tübingen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Internal Medicine, Division of Nephrology, University Hospital Tübingen, D-72076 Tübingen</wicri:regionArea><wicri:noRegion>72076 Tübingen</wicri:noRegion><wicri:noRegion>72076 Tübingen</wicri:noRegion><wicri:noRegion>D-72076 Tübingen</wicri:noRegion></affiliation></author><author><name sortKey="Newland, Ronald C" sort="Newland, Ronald C" uniqKey="Newland R" first="Ronald C." last="Newland">Ronald C. Newland</name><affiliation wicri:level="1"><nlm:aff id="A18">Department of Anatomical Pathology, Concord Hospital, Sydney, NSW, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Anatomical Pathology, Concord Hospital, Sydney, NSW</wicri:regionArea><wicri:noRegion>NSW</wicri:noRegion></affiliation></author><author><name sortKey="Wiech, Thorsten" sort="Wiech, Thorsten" uniqKey="Wiech T" first="Thorsten" last="Wiech">Thorsten Wiech</name><affiliation wicri:level="3"><nlm:aff id="A19">Institute of Pathology, University Hospital Freiburg, Freiburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, University Hospital Freiburg, Freiburg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Fribourg-en-Brisgau</region><settlement type="city">Fribourg-en-Brisgau</settlement></placeName></affiliation></author><author><name sortKey="Zschiedrich, Stefan" sort="Zschiedrich, Stefan" uniqKey="Zschiedrich S" first="Stefan" last="Zschiedrich">Stefan Zschiedrich</name><affiliation wicri:level="3"><nlm:aff id="A20">Renal Division, University Hospital Freiburg, Freiburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Renal Division, University Hospital Freiburg, Freiburg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Fribourg-en-Brisgau</region><settlement type="city">Fribourg-en-Brisgau</settlement></placeName></affiliation></author><author><name sortKey="Huber, Tobias B" sort="Huber, Tobias B" uniqKey="Huber T" first="Tobias B." last="Huber">Tobias B. Huber</name><affiliation wicri:level="3"><nlm:aff id="A20">Renal Division, University Hospital Freiburg, Freiburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Renal Division, University Hospital Freiburg, Freiburg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Fribourg-en-Brisgau</region><settlement type="city">Fribourg-en-Brisgau</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A21">BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg</wicri:regionArea><wicri:noRegion>Albert-Ludwigs-University Freiburg</wicri:noRegion><wicri:noRegion>Albert-Ludwigs-University Freiburg</wicri:noRegion><wicri:noRegion>Albert-Ludwigs-University Freiburg</wicri:noRegion></affiliation></author><author><name sortKey="Friedl, Andreas" sort="Friedl, Andreas" uniqKey="Friedl A" first="Andreas" last="Friedl">Andreas Friedl</name><affiliation><nlm:aff id="A22">Department of Pathology and Laboratory Medicine University of Wisconsin, Madison, Wisconsin USA</nlm:aff><wicri:noCountry code="subfield">Wisconsin USA</wicri:noCountry></affiliation></author><author><name sortKey="Slaats, Gisela G" sort="Slaats, Gisela G" uniqKey="Slaats G" first="Gisela G." last="Slaats">Gisela G. Slaats</name><affiliation wicri:level="3"><nlm:aff id="A23">Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Nephrology and Hypertension, University Medical Center, Utrecht</wicri:regionArea><placeName><settlement type="city">Utrecht</settlement><region nuts="2" type="province">Utrecht (province)</region></placeName></affiliation></author><author><name sortKey="Joles, Jaap A" sort="Joles, Jaap A" uniqKey="Joles J" first="Jaap A." last="Joles">Jaap A. Joles</name><affiliation wicri:level="3"><nlm:aff id="A23">Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Nephrology and Hypertension, University Medical Center, Utrecht</wicri:regionArea><placeName><settlement type="city">Utrecht</settlement><region nuts="2" type="province">Utrecht (province)</region></placeName></affiliation></author><author><name sortKey="Goldschmeding, Roel" sort="Goldschmeding, Roel" uniqKey="Goldschmeding R" first="Roel" last="Goldschmeding">Roel Goldschmeding</name><affiliation wicri:level="1"><nlm:aff id="A24">Department of Pathology, University Medical Center Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pathology, University Medical Center Utrecht</wicri:regionArea><wicri:noRegion>University Medical Center Utrecht</wicri:noRegion></affiliation></author><author><name sortKey="Washburn, Joseph" sort="Washburn, Joseph" uniqKey="Washburn J" first="Joseph" last="Washburn">Joseph Washburn</name><affiliation wicri:level="2"><nlm:aff id="A25">University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan</wicri:regionArea><placeName><region type="state">Michigan</region></placeName></affiliation></author><author><name sortKey="Giles, Rachel H" sort="Giles, Rachel H" uniqKey="Giles R" first="Rachel H." last="Giles">Rachel H. Giles</name><affiliation wicri:level="3"><nlm:aff id="A23">Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Nephrology and Hypertension, University Medical Center, Utrecht</wicri:regionArea><placeName><settlement type="city">Utrecht</settlement><region nuts="2" type="province">Utrecht (province)</region></placeName></affiliation></author><author><name sortKey="Levy, Shawn" sort="Levy, Shawn" uniqKey="Levy S" first="Shawn" last="Levy">Shawn Levy</name><affiliation wicri:level="1"><nlm:aff id="A26">HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35806, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35806</wicri:regionArea><wicri:noRegion>Alabama 35806</wicri:noRegion></affiliation></author><author><name sortKey="Smogorzewska, Agata" sort="Smogorzewska, Agata" uniqKey="Smogorzewska A" first="Agata" last="Smogorzewska">Agata Smogorzewska</name><affiliation wicri:level="2"><nlm:aff id="A2">Laboratory of Genome Maintenance, The Rockefeller University, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Genome Maintenance, The Rockefeller University, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Hildebrandt, Friedhelm" sort="Hildebrandt, Friedhelm" uniqKey="Hildebrandt F" first="Friedhelm" last="Hildebrandt">Friedhelm Hildebrandt</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A27">Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:aff id="A28">Howard Hughes Medical Institute, Chevy Chase, MD, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Howard Hughes Medical Institute, Chevy Chase, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author></analytic><series><title level="j">Nature genetics</title><idno type="ISSN">1061-4036</idno><idno type="eISSN">1546-1718</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>SUMMARY</title><p id="P2">Chronic kidney disease (CKD) represents a major health burden<sup><xref rid="R1" ref-type="bibr">1</xref></sup>. Its central feature of renal fibrosis is not well understood. By whole exome resequencing in a model disorder for renal fibrosis, nephronophthisis (NPHP), we identified mutations of <italic>Fanconi anemia-associated nuclease 1</italic> (<italic>FAN1</italic>) as causing karyomegalic interstitial nephritis (KIN). Renal histology of KIN is indistinguishable from NPHP except for the presence of karyomegaly<sup><xref rid="R2" ref-type="bibr">2</xref></sup>. FAN1 has nuclease activity, acting in DNA interstrand crosslinking (ICL) repair within the Fanconi anemia pathway of DNA damage response (DDR)<sup><xref rid="R3" ref-type="bibr">3</xref>–<xref rid="R6" ref-type="bibr">6</xref></sup>. We demonstrate that cells from individuals with <italic>FAN1</italic> mutations exhibit sensitivity to the ICL agent mitomycin C. However, they do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from patients with Fanconi anemia. We complement ICL sensitivity with wild type <italic>FAN1</italic> but not mutant cDNA from individuals with KIN. Depletion of <italic>fan1</italic> in zebrafish revealed increased DDR, apoptosis, and kidney cysts akin to NPHP. 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<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9216904</journal-id><journal-id journal-id-type="pubmed-jr-id">2419</journal-id><journal-id journal-id-type="nlm-ta">Nat Genet</journal-id><journal-id journal-id-type="iso-abbrev">Nat. Genet.</journal-id><journal-title-group><journal-title>Nature genetics</journal-title></journal-title-group><issn pub-type="ppub">1061-4036</issn><issn pub-type="epub">1546-1718</issn></journal-meta><article-meta><article-id pub-id-type="pmid">22772369</article-id><article-id pub-id-type="pmc">3412140</article-id><article-id pub-id-type="doi">10.1038/ng.2347</article-id><article-id pub-id-type="manuscript">NIHMS385548</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title><italic>FAN1</italic> mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Weibin</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref rid="FN2" ref-type="author-notes">29</xref></contrib><contrib contrib-type="author"><name><surname>Otto</surname><given-names>Edgar A.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref rid="FN2" ref-type="author-notes">29</xref></contrib><contrib contrib-type="author"><name><surname>Cluckey</surname><given-names>Andrew</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Airik</surname><given-names>Rannar</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hurd</surname><given-names>Toby W.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chaki</surname><given-names>Moumita</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Diaz</surname><given-names>Katrina</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lach</surname><given-names>Francis P.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Bennett</surname><given-names>Geoffrey R.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Gee</surname><given-names>Heon Y.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ghosh</surname><given-names>Amiya K.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Natarajan</surname><given-names>Sivakumar</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Thongthip</surname><given-names>Supawat</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Veturi</surname><given-names>Uma</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Allen</surname><given-names>Susan J.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Janssen</surname><given-names>Sabine</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ramaswami</surname><given-names>Gokul</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Dixon</surname><given-names>Joanne</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Burkhalter</surname><given-names>Felix</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Spoendlin</surname><given-names>Martin</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Moch</surname><given-names>Holger</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Mihatsch</surname><given-names>Michael J.</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Verine</surname><given-names>Jerome</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Reade</surname><given-names>Richard</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Soliman</surname><given-names>Hany</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Godin</surname><given-names>Michel</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Kiss</surname><given-names>Denes</given-names></name><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Monga</surname><given-names>Guido</given-names></name><xref ref-type="aff" rid="A13">13</xref><xref ref-type="aff" rid="A14">14</xref></contrib><contrib contrib-type="author"><name><surname>Mazzucco</surname><given-names>Gianna</given-names></name><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Amann</surname><given-names>Kerstin</given-names></name><xref ref-type="aff" rid="A16">16</xref></contrib><contrib contrib-type="author"><name><surname>Artunc</surname><given-names>Ferruh</given-names></name><xref ref-type="aff" rid="A17">17</xref></contrib><contrib contrib-type="author"><name><surname>Newland</surname><given-names>Ronald C.</given-names></name><xref ref-type="aff" rid="A18">18</xref></contrib><contrib contrib-type="author"><name><surname>Wiech</surname><given-names>Thorsten</given-names></name><xref ref-type="aff" rid="A19">19</xref></contrib><contrib contrib-type="author"><name><surname>Zschiedrich</surname><given-names>Stefan</given-names></name><xref ref-type="aff" rid="A20">20</xref></contrib><contrib contrib-type="author"><name><surname>Huber</surname><given-names>Tobias B.</given-names></name><xref ref-type="aff" rid="A20">20</xref><xref ref-type="aff" rid="A21">21</xref></contrib><contrib contrib-type="author"><name><surname>Friedl</surname><given-names>Andreas</given-names></name><xref ref-type="aff" rid="A22">22</xref></contrib><contrib contrib-type="author"><name><surname>Slaats</surname><given-names>Gisela G.</given-names></name><xref ref-type="aff" rid="A23">23</xref></contrib><contrib contrib-type="author"><name><surname>Joles</surname><given-names>Jaap A.</given-names></name><xref ref-type="aff" rid="A23">23</xref></contrib><contrib contrib-type="author"><name><surname>Goldschmeding</surname><given-names>Roel</given-names></name><xref ref-type="aff" rid="A24">24</xref></contrib><contrib contrib-type="author"><name><surname>Washburn</surname><given-names>Joseph</given-names></name><xref ref-type="aff" rid="A25">25</xref></contrib><contrib contrib-type="author"><name><surname>Giles</surname><given-names>Rachel H.</given-names></name><xref ref-type="aff" rid="A23">23</xref></contrib><contrib contrib-type="author"><name><surname>Levy</surname><given-names>Shawn</given-names></name><xref ref-type="aff" rid="A26">26</xref></contrib><contrib contrib-type="author"><name><surname>Smogorzewska</surname><given-names>Agata</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref rid="FN1" ref-type="author-notes">30</xref></contrib><contrib contrib-type="author"><name><surname>Hildebrandt</surname><given-names>Friedhelm</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A27">27</xref><xref ref-type="aff" rid="A28">28</xref><xref rid="FN1" ref-type="author-notes">30</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA</aff><aff id="A2"><label>2</label>Laboratory of Genome Maintenance, The Rockefeller University, New York, NY, USA</aff><aff id="A3"><label>3</label>Central & Southern Regional Genetic Service, Wellington Hospital, Wellington South, New Zealand</aff><aff id="A4"><label>4</label>Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland</aff><aff id="A5"><label>5</label>Merian Iselin Klinik, CH-4054, Basel, Switzerland</aff><aff id="A6"><label>6</label>Department of Pathology, University Hospital Zurich, Zurich, Switzerland</aff><aff id="A7"><label>7</label>Pathology, University Hospital Basel, Basel, Switzerland</aff><aff id="A8"><label>8</label>Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 728, F-75010 Paris, France</aff><aff id="A9"><label>9</label>Clinique Néphrologique du Pont Allant, Maubeuge, France</aff><aff id="A10"><label>10</label>Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Louis, Service de Biochimie, Paris, 75010, France</aff><aff id="A11"><label>11</label>Department of Nephrology and Hemodialysis, Rouen University Hospital, Rouen, France</aff><aff id="A12"><label>12</label>Renal Division, Kantonsspital Liestal, Liestal, Switzerland</aff><aff id="A13"><label>13</label>Department of Medical Sciences, Faculty of Medicine, University Amedeo Avogadro of the Eastern Piedmont, Novara, Italy</aff><aff id="A14"><label>14</label>Department of Pathology, Maggiore della Carità Hospital, Novara, Italy</aff><aff id="A15"><label>15</label>Department of Biomedical Sciences and Human Oncology, Faculty of Medicine, University of Torino, Italy</aff><aff id="A16"><label>16</label>Nephropathology, Department of Pathology, University of Erlangen-Nürnberg, Germany</aff><aff id="A17"><label>17</label>Department of Internal Medicine, Division of Nephrology, University Hospital Tübingen, D-72076 Tübingen, Germany</aff><aff id="A18"><label>18</label>Department of Anatomical Pathology, Concord Hospital, Sydney, NSW, Australia</aff><aff id="A19"><label>19</label>Institute of Pathology, University Hospital Freiburg, Freiburg, Germany</aff><aff id="A20"><label>20</label>Renal Division, University Hospital Freiburg, Freiburg, Germany</aff><aff id="A21"><label>21</label>BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Germany</aff><aff id="A22"><label>22</label>Department of Pathology and Laboratory Medicine University of Wisconsin, Madison, Wisconsin USA</aff><aff id="A23"><label>23</label>Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands</aff><aff id="A24"><label>24</label>Department of Pathology, University Medical Center Utrecht, The Netherlands</aff><aff id="A25"><label>25</label>University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA</aff><aff id="A26"><label>26</label>HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35806, USA</aff><aff id="A27"><label>27</label>Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA</aff><aff id="A28"><label>28</label>Howard Hughes Medical Institute, Chevy Chase, MD, USA</aff><author-notes><corresp id="FN1"><label>30</label>Correspondence should be addressed to: Friedhelm Hildebrandt, M.D., Howard Hughes Medical Institute, University of Michigan Health System, 8220C MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5646, USA, Phone: +1 734 615-7285 (office), +1 734 615-7895, -7896 (laboratories); Fax: +1 734-615-1386, -7770, <email>fhilde@umich.edu</email> or: Agata Smogorzewska, M.D., Ph.D., Assistant Professor, Head, Laboratory of Genome Maintenance, Rockefeller University, 1230 York Avenue, New York, NY 10065-6399, Office phone: (212) 327-7850, Lab phone: (212) 327-8862, Fax: (212) 327-8262, <email>asmogorzewska@rockefeller.edu</email></corresp><fn id="FN2" fn-type="equal"><label>29</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>18</day><month>6</month><year>2012</year></pub-date><pub-date pub-type="epub"><day>08</day><month>7</month><year>2012</year></pub-date><pub-date pub-type="collection"><month>8</month><year>2012</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>2</month><year>2013</year></pub-date><volume>44</volume><issue>8</issue><fpage>910</fpage><lpage>915</lpage><pmc-comment>elocation-id from pubmed: 10.1038/ng.2347</pmc-comment>
<permissions><license><license-p>Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
<uri xlink:type="simple" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</uri></license-p></license></permissions><abstract><title>SUMMARY</title><p id="P2">Chronic kidney disease (CKD) represents a major health burden<sup><xref rid="R1" ref-type="bibr">1</xref></sup>. Its central feature of renal fibrosis is not well understood. By whole exome resequencing in a model disorder for renal fibrosis, nephronophthisis (NPHP), we identified mutations of <italic>Fanconi anemia-associated nuclease 1</italic> (<italic>FAN1</italic>) as causing karyomegalic interstitial nephritis (KIN). Renal histology of KIN is indistinguishable from NPHP except for the presence of karyomegaly<sup><xref rid="R2" ref-type="bibr">2</xref></sup>. FAN1 has nuclease activity, acting in DNA interstrand crosslinking (ICL) repair within the Fanconi anemia pathway of DNA damage response (DDR)<sup><xref rid="R3" ref-type="bibr">3</xref>–<xref rid="R6" ref-type="bibr">6</xref></sup>. We demonstrate that cells from individuals with <italic>FAN1</italic> mutations exhibit sensitivity to the ICL agent mitomycin C. However, they do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from patients with Fanconi anemia. We complement ICL sensitivity with wild type <italic>FAN1</italic> but not mutant cDNA from individuals with KIN. Depletion of <italic>fan1</italic> in zebrafish revealed increased DDR, apoptosis, and kidney cysts akin to NPHP. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms of renal fibrosis and CKD.</p></abstract></article-meta></front><floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><title>Renal histology in individuals with karyomegalic interstitial nephritis (KIN)</title><p>Renal histology of individuals with <italic>FAN1</italic> mutation exhibits the characteristic triad of nephronophthisis (NPHP), with cystic dilation of renal tubules (asterisks), interstitial infiltrations (encircled with a dotted line in <bold>a</bold>), and widespread fibrosis (blue-grey coloring in Trichrome-Masson staining in <bold>b</bold>). Karyomegaly is observed (white arrow heads in <bold>b</bold> and <bold>c</bold>) in tubules that have lost epithelial cells at their circumference (black arrow heads in <bold>b</bold> and <bold>c</bold>). The tubular basement membrane is thickened (double arrows in <bold>c</bold>) as well as attenuated (black arrow in <bold>c</bold>). <bold>a</bold> and <bold>b</bold> are from individual A4393-21, <bold>c</bold> is from individual A4466-21. Scale bars denote 100 μm.</p></caption><graphic xlink:href="nihms385548f1"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><title>Phenotypes of <italic>FAN1</italic>-mutant cells</title><p>(<bold>a</bold>) Western blot analysis with anti-FAN1 antibody raised against the N-terminal 90 amino acids of FAN1. Specificity of the antibody was confirmed by the abrogation of signal after transduction of BJ fibroblasts with shRNAs against <italic>FAN1</italic> and in individuals with protein truncating mutations in <italic>FAN1</italic> (see <xref rid="T1" ref-type="table">Table 1</xref>). (<bold>b</bold>) Examples of metaphases of the indicated cell lines after treatment with 50 nM mitomycin C (MMC). Arrows indicate radial chromosomes, arrowheads indicate chromatid breaks. (<bold>c</bold>–<bold>f</bold>) MMC and diepoxybutane (DEB) sensitivity of the indicated <italic>FAN1</italic>-mutant cell lines in comparison to <italic>FANCA</italic> mutant and wild type cell lines. Primary fibroblast (FIB) (<bold>c</bold> and <bold>d</bold>) or lymphoblastoid cell lines (LCL) (<bold>e</bold> and <bold>f</bold>) were treated in triplicate with increasing levels of indicated DNA ICL inducing agent. After 6 or 8 days, cell numbers were determined using a Coulter counter. Total cell numbers at each dose were divided by the number of cells in the initial untreated sample to arrive at percent survival. Error bars indicate standard deviations. (<bold>g</bold>) Cell cycle analysis of the indicated fibroblast cell lines after treatment with 100 nM MMC or 0.1 μg of DEB per ml of media. Untreated samples were analyzed in parallel.</p></caption><graphic xlink:href="nihms385548f2"></graphic></fig><fig id="F3" orientation="portrait" position="float"><label>Figure 3</label><caption><title>Complementation of <italic>FAN1</italic>-mutant cells with <italic>FAN1</italic> cDNAs, and epistasis analysis with genes implicated in ICL resistance</title><p>(<bold>a</bold>) Complementation of MMC sensitivity in fibroblasts of KIN individual A1170-22. Fibroblasts stably transduced with empty vector (vector control), vector expressing wild type <italic>FAN1</italic> cDNA, or <italic>FAN1</italic> cDNA with mutations incorporated (see <xref rid="T1" ref-type="table">Table 1</xref>) were exposed to different levels of MMC ranging from 0–100 nM. After 8 days, the cell number was determined using a Coulter counter. Total cell numbers at each dose were divided by the number of cells in the initial untreated sample to arrive at percent survival. Error bars indicate s.d. (<bold>b</bold>) Immunoblot showing expression levels of <italic>FAN1</italic> alleles in A1170-22 fibroblasts used in the MMC sensitivity assay shown in panel <bold>a</bold>. Note that Trp707* and Arg679Thrfs*5 lack expression of FAN1 and Leu925Profs*25 results in a shortened product. (<bold>c</bold>) MMC sensitivity in A1170-22 fibroblasts transfected with the indicated siRNAs. (<bold>d</bold>) Immunoblot of expression levels of indicated proteins after siRNA-mediated depletion in the A1170-22 fibroblasts used in the experiment shown in panel <bold>c</bold>.</p></caption><graphic xlink:href="nihms385548f3"></graphic></fig><fig id="F4" orientation="portrait" position="float"><label>Figure 4</label><caption><title>Phenotype of <italic>fan1</italic> loss of function in zebrafish</title><p>(<bold>a</bold>–<bold>c</bold>) Knockdown of <italic>fan1</italic> in zebrafish causes developmental abnormalities. A <italic>fan1</italic>D7 morpholino (MO) that targets the splice acceptor site of exon 7 (<xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 5</xref>) was injected into 1–4 cell stage embryos at the concentrations shown. Standard control MO (Ctrl) was injected at 0.2 mM. At 25 hpf (<bold>b</bold>–<bold>c</bold>), morphant embryos displayed shortened body axis, ventral body axis curvature, and massive cell death (dark grey tissue areas) throughout the embryo (see <bold>c</bold>), when compared to control MO (<bold>a</bold>). Scale bar in <bold>a</bold>–<bold>c</bold> is 750 μm for left panels and 150 μm for right panels.</p><p>(<bold>d</bold>–<bold>e</bold>) Knockdown of <italic>fan1</italic> in zebrafish induces widespread apoptosis. Upon <italic>fan1</italic> knockdown, utilizing <italic>fan1</italic>D7 MO as in (<bold>a</bold>–<bold>c</bold>), widespread apoptosis was seen in the anterior body (<bold>d</bold>) and the tail (<xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 5</xref>) of 27 hpf zebrafish, as detected by an antibody against activated caspase-3 (CASP3) compared to negative control morpholino. Images are representative for 32 embryos evaluated for control and MO knockdown, respectively. (<bold>e</bold>) Knockdown of <italic>fan1</italic> leads to increased staining with γH2AX antibody, indicating increased DDR. In knockdown embryos, 24 out of 27 embryos had elevated Caspase-3 staining, and 27 of 32 embryos stained with γH2AX had elevated expression of γH2AX. Scale bar is 250 μm. (See also <xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 5</xref>.)</p><p>(<bold>f</bold>–<bold>h</bold>) Knockdown of <italic>fan1</italic> on the background of p53 morphants reveals pronephric cysts. (<bold>f</bold>) <italic>p53</italic> knockdown alone does not cause pronephric cysts in 72 hpf embryos exhibiting normal pronephric tubules (arrows). (<bold>g</bold>) However, 72 hpf zebrafish embryos co-injected with <italic>fan1D7</italic> MO (0.1 mM) and <italic>p53</italic> MO (0.2 mM) display pronephric kidney cysts (19±3%) (asterisks in <bold>g</bold>) and results in body axis curvature (not shown) (45±4%). (<bold>g</bold>–<bold>h</bold>) it causes body axis curvature in a significantly smaller fraction (11±2%; not shown). Scale bar is 50 μm.</p></caption><graphic xlink:href="nihms385548f4"></graphic></fig><fig id="F5" orientation="portrait" position="float"><label>Figure 5</label><caption><title>Differential expression levels of <italic>FANCD2 vs. FAN1</italic> in human tissue sources and increased DNA damage response in chronic kidney disease</title><p>Expression levels measured by quantitative real-time PCR were normalized against <italic>GAPDH</italic> expression. Error bars show SEM of triplicates.</p><p>(<bold>a</bold>–<bold>b</bold>) Expression levels of <italic>FANCD2 vs. FAN1</italic> in 25 different human tissue sources (of 48 total with differential expression). (<bold>a</bold>) <italic>FAN1</italic> expression exceeded <italic>FANCD2</italic> in parenchymatous organs including kidney, liver, neuronal tissue and female reproductive organs, whereas (<bold>b</bold>) <italic>FANCD2</italic> expression exceeds <italic>FAN1</italic> expression in lymphatic or bone marrow-derived sources, skin and testis.</p><p>(<bold>c</bold>–<bold>h</bold>) DNA damage response is pronounced in chronic kidney disease.</p><p>(<bold>c</bold>) Quantified percent of γ-H2AX staining of fawn-hooded hypertensive rat kidneys (between 2,000–3,000 cells scored per animal) with progressive kidney injury<sup><xref rid="R31" ref-type="bibr">31</xref></sup> correlates with proteinuria (p<0.0054).</p><p>(<bold>d</bold>) Example of γ-H2AX immunostaining in normal rat kidney.</p><p>(<bold>e</bold>) Example of chronically damaged kidney in the fawn hooded hypertensive rat.</p><p>(<bold>f</bold>–<bold>h</bold>) γ-H2AX staining of human kidney transplant biopsies: Transplant kidney, 4 months post-transplantation, no evidence for injury (<bold>f</bold>); transplant kidney, 16 yrs after transplantation, chronic damage (<bold>g</bold>); transplant kidney with chronic tissue damage, 10 years post-transplantation (<bold>h</bold>). Scale bars in <bold>d</bold>–<bold>h</bold> are 100 μm.</p></caption><graphic xlink:href="nihms385548f5"></graphic></fig><table-wrap id="T1" position="float" orientation="landscape"><label>Table 1</label><caption><p>Mutations of <italic>FAN1</italic> in 9 families with karyomegalic interstitial nephritis.</p></caption><table frame="box" rules="all"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1">Family-Individual</th><th valign="top" align="center" rowspan="1" colspan="1">Ethnic origin</th><th valign="top" align="center" rowspan="1" colspan="1">Nucleotide alteration<xref rid="TFN1" ref-type="table-fn">a</xref>,<xref rid="TFN2" ref-type="table-fn">b</xref></th><th valign="top" align="center" rowspan="1" colspan="1">Deduced protein change</th><th valign="top" align="center" rowspan="1" colspan="1">Exon/Intron (state)</th><th valign="top" align="center" rowspan="1" colspan="1">Continuous amino acid sequence conservation</th><th valign="top" align="center" rowspan="1" colspan="1">Parental consan-guinity</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">A4385<break></break> -21 (no DNA) <break></break> -22</td><td align="center" valign="top" rowspan="1" colspan="1">French</td><td align="center" valign="top" rowspan="1" colspan="1"><underline>c.1234+2T>A</underline><break></break>c.2036_7delGA</td><td align="center" valign="top" rowspan="1" colspan="1">Splice site<break></break>p.Arg679Thrfs*5</td><td align="center" valign="top" rowspan="1" colspan="1">2 (het) <break></break>7 (het)</td><td align="center" valign="top" rowspan="1" colspan="1">N/A<break></break>N/A</td><td align="center" valign="top" rowspan="1" colspan="1">No</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">A4466<break></break> -21</td><td align="center" valign="top" rowspan="1" colspan="1">French</td><td align="center" valign="top" rowspan="1" colspan="1"><underline>c.1234+2T>A</underline><break></break>c.2245C>T</td><td align="center" valign="top" rowspan="1" colspan="1">Splice site<break></break>p.Arg749*</td><td align="center" valign="top" rowspan="1" colspan="1">2 (het) <break></break>9 (het)</td><td align="center" valign="top" rowspan="1" colspan="1">N/A<break></break>N/A</td><td align="center" valign="top" rowspan="1" colspan="1">No</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">A4393<break></break> -21</td><td align="center" valign="top" rowspan="1" colspan="1">French</td><td align="center" valign="top" rowspan="1" colspan="1">c.1375+1G>A<break></break><graphic xlink:href="nihms385548t1"></graphic></td><td align="center" valign="top" rowspan="1" colspan="1">Splice site<break></break>p.Asp873Thrfs*17</td><td align="center" valign="top" rowspan="1" colspan="1">3 (het) <break></break>12 (het)</td><td align="center" valign="top" rowspan="1" colspan="1">N/A<break></break>N/A</td><td align="center" valign="top" rowspan="1" colspan="1">No</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">A4605<break></break> -21</td><td align="center" valign="top" rowspan="1" colspan="1">German</td><td align="center" valign="top" rowspan="1" colspan="1"><graphic xlink:href="nihms385548t2"></graphic><break></break>c.2786A>C</td><td align="center" valign="top" rowspan="1" colspan="1">p.Arg536*<break></break>p.Gln929Pro</td><td align="center" valign="top" rowspan="1" colspan="1">5 (het) <break></break>12 (het)</td><td align="center" valign="top" rowspan="1" colspan="1">N/A<break></break><italic>D. rerio</italic><xref rid="TFN3" ref-type="table-fn">c</xref></td><td align="center" valign="top" rowspan="1" colspan="1">No</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">A4486<break></break> -22<break></break> -23</td><td align="center" valign="top" rowspan="1" colspan="1">German</td><td align="center" valign="top" rowspan="1" colspan="1"><graphic xlink:href="nihms385548t3"></graphic></td><td align="center" valign="top" rowspan="1" colspan="1">p.Arg536*<break></break>p.Asp960Asn</td><td align="center" valign="top" rowspan="1" colspan="1">5 (het) <break></break>13 (het)</td><td align="center" valign="top" rowspan="1" colspan="1">N/A<break></break><italic>S. pombe</italic><xref rid="TFN3" ref-type="table-fn">c</xref></td><td align="center" valign="top" rowspan="1" colspan="1">No</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">A1170<break></break> -22<break></break> -25</td><td align="center" valign="top" rowspan="1" colspan="1">New Zealand<break></break>Maori</td><td align="center" valign="top" rowspan="1" colspan="1">c.2120G>A</td><td align="center" valign="top" rowspan="1" colspan="1">p.Trp707*</td><td align="center" valign="top" rowspan="1" colspan="1">8 (hom)</td><td align="center" valign="top" rowspan="1" colspan="1">N/A</td><td align="center" valign="top" rowspan="1" colspan="1">distant?</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">A4433<break></break> -21</td><td align="center" valign="top" rowspan="1" colspan="1">Spanish</td><td align="center" valign="top" rowspan="1" colspan="1"><graphic xlink:href="nihms385548t4"></graphic></td><td align="center" valign="top" rowspan="1" colspan="1">p.Asp873Thrfs*17</td><td align="center" valign="top" rowspan="1" colspan="1">12 (hom)</td><td align="center" valign="top" rowspan="1" colspan="1">N/A</td><td align="center" valign="top" rowspan="1" colspan="1">No</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">A4407<break></break> -24</td><td align="center" valign="top" rowspan="1" colspan="1">Swiss</td><td align="center" valign="top" rowspan="1" colspan="1">c.2611T>C<break></break><graphic xlink:href="nihms385548t5"></graphic></td><td align="center" valign="top" rowspan="1" colspan="1">p.Cys871Arg<break></break>p.Asp960Asn</td><td align="center" valign="top" rowspan="1" colspan="1">12 (het) <break></break>13 (het)</td><td align="center" valign="top" rowspan="1" colspan="1">(never “R”)<xref rid="TFN4" ref-type="table-fn">d</xref><break></break><italic>S. pombe</italic><xref rid="TFN3" ref-type="table-fn">c</xref></td><td align="center" valign="top" rowspan="1" colspan="1">No</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">A4333<break></break> -21</td><td align="center" valign="top" rowspan="1" colspan="1">ND</td><td align="center" valign="top" rowspan="1" colspan="1">c.2774_5delTT<break></break>c.2810G>A</td><td align="center" valign="top" rowspan="1" colspan="1">p.Leu925Profs*25<break></break>p.Gly937Asp</td><td align="center" valign="top" rowspan="1" colspan="1">12 (het) <break></break>13 (het)</td><td align="center" valign="top" rowspan="1" colspan="1">N/A<break></break><italic>C. intestinalis</italic><xref rid="TFN3" ref-type="table-fn">c</xref></td><td align="center" valign="top" rowspan="1" colspan="1">No</td></tr></tbody></table><table-wrap-foot><fn id="TFN1"><label>a</label><p>Four different European founder mutations are underlined.</p></fn><fn id="TFN2"><label>b</label><p><italic>FAN1</italic> cDNA mutations are numbered according to human cDNA reference sequence NM_014967.4, where +1 corresponds to the A of ATG start translation codon. First exon is non-coding.</p></fn><fn id="TFN3"><label>c</label><p>Amino acid residue is continually conserved throughout evolution, including <italic>Danio rerio</italic>, <italic>Saccharomyces pombe,</italic> or <italic>Ciona intestinalis</italic>, as indicated.</p></fn><fn id="TFN4"><label>d</label><p>Amino acid residue is not conserved in evolution, but never substituted by an “R”.</p></fn><fn id="TFN5"><p>hom, homozygous; het, heterozygous; N/A, not applicable; ND, no data</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>France</li><li>Italie</li><li>Nouvelle-Zélande</li><li>Pays-Bas</li><li>Suisse</li><li>États-Unis</li></country><region><li>Bade-Wurtemberg</li><li>District de Fribourg-en-Brisgau</li><li>Haute-Normandie</li><li>Maryland</li><li>Michigan</li><li>Région Normandie</li><li>Utrecht (province)</li><li>État de New York</li></region><settlement><li>Fribourg-en-Brisgau</li><li>Rouen</li><li>Utrecht</li></settlement></list><tree><noCountry><name sortKey="Friedl, Andreas" sort="Friedl, Andreas" uniqKey="Friedl A" first="Andreas" last="Friedl">Andreas Friedl</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Zhou, Weibin" sort="Zhou, Weibin" uniqKey="Zhou W" first="Weibin" last="Zhou">Weibin Zhou</name></noRegion><name sortKey="Airik, Rannar" sort="Airik, Rannar" uniqKey="Airik R" first="Rannar" last="Airik">Rannar Airik</name><name sortKey="Allen, Susan J" sort="Allen, Susan J" uniqKey="Allen S" first="Susan J." last="Allen">Susan J. Allen</name><name sortKey="Bennett, Geoffrey R" sort="Bennett, Geoffrey R" uniqKey="Bennett G" first="Geoffrey R." last="Bennett">Geoffrey R. Bennett</name><name sortKey="Chaki, Moumita" sort="Chaki, Moumita" uniqKey="Chaki M" first="Moumita" last="Chaki">Moumita Chaki</name><name sortKey="Cluckey, Andrew" sort="Cluckey, Andrew" uniqKey="Cluckey A" first="Andrew" last="Cluckey">Andrew Cluckey</name><name sortKey="Diaz, Katrina" sort="Diaz, Katrina" uniqKey="Diaz K" first="Katrina" last="Diaz">Katrina Diaz</name><name sortKey="Gee, Heon Y" sort="Gee, Heon Y" uniqKey="Gee H" first="Heon Y." last="Gee">Heon Y. Gee</name><name sortKey="Ghosh, Amiya K" sort="Ghosh, Amiya K" uniqKey="Ghosh A" first="Amiya K." last="Ghosh">Amiya K. Ghosh</name><name sortKey="Hildebrandt, Friedhelm" sort="Hildebrandt, Friedhelm" uniqKey="Hildebrandt F" first="Friedhelm" last="Hildebrandt">Friedhelm Hildebrandt</name><name sortKey="Hildebrandt, Friedhelm" sort="Hildebrandt, Friedhelm" uniqKey="Hildebrandt F" first="Friedhelm" last="Hildebrandt">Friedhelm Hildebrandt</name><name sortKey="Hildebrandt, Friedhelm" sort="Hildebrandt, Friedhelm" uniqKey="Hildebrandt F" first="Friedhelm" last="Hildebrandt">Friedhelm Hildebrandt</name><name sortKey="Hurd, Toby W" sort="Hurd, Toby W" uniqKey="Hurd T" first="Toby W." last="Hurd">Toby W. Hurd</name><name sortKey="Janssen, Sabine" sort="Janssen, Sabine" uniqKey="Janssen S" first="Sabine" last="Janssen">Sabine Janssen</name><name sortKey="Lach, Francis P" sort="Lach, Francis P" uniqKey="Lach F" first="Francis P." last="Lach">Francis P. Lach</name><name sortKey="Levy, Shawn" sort="Levy, Shawn" uniqKey="Levy S" first="Shawn" last="Levy">Shawn Levy</name><name sortKey="Natarajan, Sivakumar" sort="Natarajan, Sivakumar" uniqKey="Natarajan S" first="Sivakumar" last="Natarajan">Sivakumar Natarajan</name><name sortKey="Otto, Edgar A" sort="Otto, Edgar A" uniqKey="Otto E" first="Edgar A." last="Otto">Edgar A. Otto</name><name sortKey="Ramaswami, Gokul" sort="Ramaswami, Gokul" uniqKey="Ramaswami G" first="Gokul" last="Ramaswami">Gokul Ramaswami</name><name sortKey="Smogorzewska, Agata" sort="Smogorzewska, Agata" uniqKey="Smogorzewska A" first="Agata" last="Smogorzewska">Agata Smogorzewska</name><name sortKey="Thongthip, Supawat" sort="Thongthip, Supawat" uniqKey="Thongthip S" first="Supawat" last="Thongthip">Supawat Thongthip</name><name sortKey="Veturi, Uma" sort="Veturi, Uma" uniqKey="Veturi U" first="Uma" last="Veturi">Uma Veturi</name><name sortKey="Washburn, Joseph" sort="Washburn, Joseph" uniqKey="Washburn J" first="Joseph" last="Washburn">Joseph Washburn</name></country><country name="Nouvelle-Zélande"><noRegion><name sortKey="Dixon, Joanne" sort="Dixon, Joanne" uniqKey="Dixon J" first="Joanne" last="Dixon">Joanne Dixon</name></noRegion></country><country name="Suisse"><noRegion><name sortKey="Burkhalter, Felix" sort="Burkhalter, Felix" uniqKey="Burkhalter F" first="Felix" last="Burkhalter">Felix Burkhalter</name></noRegion><name sortKey="Kiss, Denes" sort="Kiss, Denes" uniqKey="Kiss D" first="Denes" last="Kiss">Denes Kiss</name><name sortKey="Mihatsch, Michael J" sort="Mihatsch, Michael J" uniqKey="Mihatsch M" first="Michael J." last="Mihatsch">Michael J. Mihatsch</name><name sortKey="Moch, Holger" sort="Moch, Holger" uniqKey="Moch H" first="Holger" last="Moch">Holger Moch</name><name sortKey="Spoendlin, Martin" sort="Spoendlin, Martin" uniqKey="Spoendlin M" first="Martin" last="Spoendlin">Martin Spoendlin</name></country><country name="France"><noRegion><name sortKey="Verine, Jerome" sort="Verine, Jerome" uniqKey="Verine J" first="Jerome" last="Verine">Jerome Verine</name></noRegion><name sortKey="Godin, Michel" sort="Godin, Michel" uniqKey="Godin M" first="Michel" last="Godin">Michel Godin</name><name sortKey="Reade, Richard" sort="Reade, Richard" uniqKey="Reade R" first="Richard" last="Reade">Richard Reade</name><name sortKey="Soliman, Hany" sort="Soliman, Hany" uniqKey="Soliman H" first="Hany" last="Soliman">Hany Soliman</name></country><country name="Italie"><noRegion><name sortKey="Monga, Guido" sort="Monga, Guido" uniqKey="Monga G" first="Guido" last="Monga">Guido Monga</name></noRegion><name sortKey="Mazzucco, Gianna" sort="Mazzucco, Gianna" uniqKey="Mazzucco G" first="Gianna" last="Mazzucco">Gianna Mazzucco</name><name sortKey="Monga, Guido" sort="Monga, Guido" uniqKey="Monga G" first="Guido" last="Monga">Guido Monga</name></country><country name="Allemagne"><noRegion><name sortKey="Amann, Kerstin" sort="Amann, Kerstin" uniqKey="Amann K" first="Kerstin" last="Amann">Kerstin Amann</name></noRegion><name sortKey="Artunc, Ferruh" sort="Artunc, Ferruh" uniqKey="Artunc F" first="Ferruh" last="Artunc">Ferruh Artunc</name><name sortKey="Huber, Tobias B" sort="Huber, Tobias B" uniqKey="Huber T" first="Tobias B." last="Huber">Tobias B. Huber</name><name sortKey="Huber, Tobias B" sort="Huber, Tobias B" uniqKey="Huber T" first="Tobias B." last="Huber">Tobias B. Huber</name><name sortKey="Wiech, Thorsten" sort="Wiech, Thorsten" uniqKey="Wiech T" first="Thorsten" last="Wiech">Thorsten Wiech</name><name sortKey="Zschiedrich, Stefan" sort="Zschiedrich, Stefan" uniqKey="Zschiedrich S" first="Stefan" last="Zschiedrich">Stefan Zschiedrich</name></country><country name="Australie"><noRegion><name sortKey="Newland, Ronald C" sort="Newland, Ronald C" uniqKey="Newland R" first="Ronald C." last="Newland">Ronald C. Newland</name></noRegion></country><country name="Pays-Bas"><region name="Utrecht (province)"><name sortKey="Slaats, Gisela G" sort="Slaats, Gisela G" uniqKey="Slaats G" first="Gisela G." last="Slaats">Gisela G. Slaats</name></region><name sortKey="Giles, Rachel H" sort="Giles, Rachel H" uniqKey="Giles R" first="Rachel H." last="Giles">Rachel H. Giles</name><name sortKey="Goldschmeding, Roel" sort="Goldschmeding, Roel" uniqKey="Goldschmeding R" first="Roel" last="Goldschmeding">Roel Goldschmeding</name><name sortKey="Joles, Jaap A" sort="Joles, Jaap A" uniqKey="Joles J" first="Jaap A." last="Joles">Jaap A. Joles</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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