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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mutations in <italic>SLC33A1</italic> Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin</title><author><name sortKey="Huppke, Peter" sort="Huppke, Peter" uniqKey="Huppke P" first="Peter" last="Huppke">Peter Huppke</name><affiliation><nlm:aff id="aff1">Department of Pediatrics and Pediatric Neurology, Georg August University, 37075 Göttingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Brendel, Cornelia" sort="Brendel, Cornelia" uniqKey="Brendel C" first="Cornelia" last="Brendel">Cornelia Brendel</name><affiliation><nlm:aff id="aff1">Department of Pediatrics and Pediatric Neurology, Georg August University, 37075 Göttingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Kalscheuer, Vera" sort="Kalscheuer, Vera" uniqKey="Kalscheuer V" first="Vera" last="Kalscheuer">Vera Kalscheuer</name><affiliation><nlm:aff id="aff2">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Korenke, Georg Christoph" sort="Korenke, Georg Christoph" uniqKey="Korenke G" first="Georg Christoph" last="Korenke">Georg Christoph Korenke</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics, Children's Hospital, 26133 Oldenburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Marquardt, Iris" sort="Marquardt, Iris" uniqKey="Marquardt I" first="Iris" last="Marquardt">Iris Marquardt</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics, Children's Hospital, 26133 Oldenburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Freisinger, Peter" sort="Freisinger, Peter" uniqKey="Freisinger P" first="Peter" last="Freisinger">Peter Freisinger</name><affiliation><nlm:aff id="aff4">Department of Pediatrics, Klinikum am Steinenberg, 72764 Reutlingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Christodoulou, John" sort="Christodoulou, John" uniqKey="Christodoulou J" first="John" last="Christodoulou">John Christodoulou</name><affiliation><nlm:aff id="aff5">Western Sydney Genetics Program, The Children's Hospital at Westmead, and Disciplines of Paediatrics and Child Health and Genetic Medicine, Sydney Medical School, University of Sydney, 2145 Westmead, Australia</nlm:aff></affiliation></author><author><name sortKey="Hillebrand, Merle" sort="Hillebrand, Merle" uniqKey="Hillebrand M" first="Merle" last="Hillebrand">Merle Hillebrand</name><affiliation><nlm:aff id="aff1">Department of Pediatrics and Pediatric Neurology, Georg August University, 37075 Göttingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Pitelet, Gaele" sort="Pitelet, Gaele" uniqKey="Pitelet G" first="Gaele" last="Pitelet">Gaele Pitelet</name><affiliation><nlm:aff id="aff6">Service de Neuropédiatrie, CHU Nice, 6200 Nice, France</nlm:aff></affiliation></author><author><name sortKey="Wilson, Callum" sort="Wilson, Callum" uniqKey="Wilson C" first="Callum" last="Wilson">Callum Wilson</name><affiliation><nlm:aff id="aff7">National Metabolic Service, Starship Children's Hospital, 1142 Auckland, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Gruber Sedlmayr, Ursula" sort="Gruber Sedlmayr, Ursula" uniqKey="Gruber Sedlmayr U" first="Ursula" last="Gruber-Sedlmayr">Ursula Gruber-Sedlmayr</name><affiliation><nlm:aff id="aff8">Department of Pediatrics, Medical University of Graz, 8010 Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Ullmann, Reinhard" sort="Ullmann, Reinhard" uniqKey="Ullmann R" first="Reinhard" last="Ullmann">Reinhard Ullmann</name><affiliation><nlm:aff id="aff2">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Haas, Stefan" sort="Haas, Stefan" uniqKey="Haas S" first="Stefan" last="Haas">Stefan Haas</name><affiliation><nlm:aff id="aff9">Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Elpeleg, Orly" sort="Elpeleg, Orly" uniqKey="Elpeleg O" first="Orly" last="Elpeleg">Orly Elpeleg</name><affiliation><nlm:aff id="aff10">Monique and Jacques Roboh Department of Genetic Research, Department of Genetic and Metabolic Diseases, Hadassah, Hebrew University Medical Center, 91050 Jerusalem, Israel</nlm:aff></affiliation></author><author><name sortKey="Nurnberg, Gudrun" sort="Nurnberg, Gudrun" uniqKey="Nurnberg G" first="Gudrun" last="Nürnberg">Gudrun Nürnberg</name><affiliation><nlm:aff id="aff11">Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany</nlm:aff></affiliation></author><author><name sortKey="Nurnberg, Peter" sort="Nurnberg, Peter" uniqKey="Nurnberg P" first="Peter" last="Nürnberg">Peter Nürnberg</name><affiliation><nlm:aff id="aff11">Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany</nlm:aff></affiliation></author><author><name sortKey="Dad, Shzeena" sort="Dad, Shzeena" uniqKey="Dad S" first="Shzeena" last="Dad">Shzeena Dad</name><affiliation><nlm:aff id="aff12">Department for Applied Human Molecular Genetics Kennedy Center, 2600 Glostrup, Denmark</nlm:aff></affiliation></author><author><name sortKey="M Ller, Lisbeth Birk" sort="M Ller, Lisbeth Birk" uniqKey="M Ller L" first="Lisbeth Birk" last="M Ller">Lisbeth Birk M Ller</name><affiliation><nlm:aff id="aff12">Department for Applied Human Molecular Genetics Kennedy Center, 2600 Glostrup, Denmark</nlm:aff></affiliation></author><author><name sortKey="Kaler, Stephen G" sort="Kaler, Stephen G" uniqKey="Kaler S" first="Stephen G." last="Kaler">Stephen G. Kaler</name><affiliation><nlm:aff id="aff13">Unit on Human Copper Metabolism, Molecular Medicine Program, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA</nlm:aff></affiliation></author><author><name sortKey="G Rtner, Jutta" sort="G Rtner, Jutta" uniqKey="G Rtner J" first="Jutta" last="G Rtner">Jutta G Rtner</name><affiliation><nlm:aff id="aff1">Department of Pediatrics and Pediatric Neurology, Georg August University, 37075 Göttingen, Germany</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22243965</idno><idno type="pmc">3257879</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257879</idno><idno type="RBID">PMC:3257879</idno><idno type="doi">10.1016/j.ajhg.2011.11.030</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">001700</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001700</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutations in <italic>SLC33A1</italic> Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin</title><author><name sortKey="Huppke, Peter" sort="Huppke, Peter" uniqKey="Huppke P" first="Peter" last="Huppke">Peter Huppke</name><affiliation><nlm:aff id="aff1">Department of Pediatrics and Pediatric Neurology, Georg August University, 37075 Göttingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Brendel, Cornelia" sort="Brendel, Cornelia" uniqKey="Brendel C" first="Cornelia" last="Brendel">Cornelia Brendel</name><affiliation><nlm:aff id="aff1">Department of Pediatrics and Pediatric Neurology, Georg August University, 37075 Göttingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Kalscheuer, Vera" sort="Kalscheuer, Vera" uniqKey="Kalscheuer V" first="Vera" last="Kalscheuer">Vera Kalscheuer</name><affiliation><nlm:aff id="aff2">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Korenke, Georg Christoph" sort="Korenke, Georg Christoph" uniqKey="Korenke G" first="Georg Christoph" last="Korenke">Georg Christoph Korenke</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics, Children's Hospital, 26133 Oldenburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Marquardt, Iris" sort="Marquardt, Iris" uniqKey="Marquardt I" first="Iris" last="Marquardt">Iris Marquardt</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics, Children's Hospital, 26133 Oldenburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Freisinger, Peter" sort="Freisinger, Peter" uniqKey="Freisinger P" first="Peter" last="Freisinger">Peter Freisinger</name><affiliation><nlm:aff id="aff4">Department of Pediatrics, Klinikum am Steinenberg, 72764 Reutlingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Christodoulou, John" sort="Christodoulou, John" uniqKey="Christodoulou J" first="John" last="Christodoulou">John Christodoulou</name><affiliation><nlm:aff id="aff5">Western Sydney Genetics Program, The Children's Hospital at Westmead, and Disciplines of Paediatrics and Child Health and Genetic Medicine, Sydney Medical School, University of Sydney, 2145 Westmead, Australia</nlm:aff></affiliation></author><author><name sortKey="Hillebrand, Merle" sort="Hillebrand, Merle" uniqKey="Hillebrand M" first="Merle" last="Hillebrand">Merle Hillebrand</name><affiliation><nlm:aff id="aff1">Department of Pediatrics and Pediatric Neurology, Georg August University, 37075 Göttingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Pitelet, Gaele" sort="Pitelet, Gaele" uniqKey="Pitelet G" first="Gaele" last="Pitelet">Gaele Pitelet</name><affiliation><nlm:aff id="aff6">Service de Neuropédiatrie, CHU Nice, 6200 Nice, France</nlm:aff></affiliation></author><author><name sortKey="Wilson, Callum" sort="Wilson, Callum" uniqKey="Wilson C" first="Callum" last="Wilson">Callum Wilson</name><affiliation><nlm:aff id="aff7">National Metabolic Service, Starship Children's Hospital, 1142 Auckland, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Gruber Sedlmayr, Ursula" sort="Gruber Sedlmayr, Ursula" uniqKey="Gruber Sedlmayr U" first="Ursula" last="Gruber-Sedlmayr">Ursula Gruber-Sedlmayr</name><affiliation><nlm:aff id="aff8">Department of Pediatrics, Medical University of Graz, 8010 Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Ullmann, Reinhard" sort="Ullmann, Reinhard" uniqKey="Ullmann R" first="Reinhard" last="Ullmann">Reinhard Ullmann</name><affiliation><nlm:aff id="aff2">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Haas, Stefan" sort="Haas, Stefan" uniqKey="Haas S" first="Stefan" last="Haas">Stefan Haas</name><affiliation><nlm:aff id="aff9">Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Elpeleg, Orly" sort="Elpeleg, Orly" uniqKey="Elpeleg O" first="Orly" last="Elpeleg">Orly Elpeleg</name><affiliation><nlm:aff id="aff10">Monique and Jacques Roboh Department of Genetic Research, Department of Genetic and Metabolic Diseases, Hadassah, Hebrew University Medical Center, 91050 Jerusalem, Israel</nlm:aff></affiliation></author><author><name sortKey="Nurnberg, Gudrun" sort="Nurnberg, Gudrun" uniqKey="Nurnberg G" first="Gudrun" last="Nürnberg">Gudrun Nürnberg</name><affiliation><nlm:aff id="aff11">Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany</nlm:aff></affiliation></author><author><name sortKey="Nurnberg, Peter" sort="Nurnberg, Peter" uniqKey="Nurnberg P" first="Peter" last="Nürnberg">Peter Nürnberg</name><affiliation><nlm:aff id="aff11">Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany</nlm:aff></affiliation></author><author><name sortKey="Dad, Shzeena" sort="Dad, Shzeena" uniqKey="Dad S" first="Shzeena" last="Dad">Shzeena Dad</name><affiliation><nlm:aff id="aff12">Department for Applied Human Molecular Genetics Kennedy Center, 2600 Glostrup, Denmark</nlm:aff></affiliation></author><author><name sortKey="M Ller, Lisbeth Birk" sort="M Ller, Lisbeth Birk" uniqKey="M Ller L" first="Lisbeth Birk" last="M Ller">Lisbeth Birk M Ller</name><affiliation><nlm:aff id="aff12">Department for Applied Human Molecular Genetics Kennedy Center, 2600 Glostrup, Denmark</nlm:aff></affiliation></author><author><name sortKey="Kaler, Stephen G" sort="Kaler, Stephen G" uniqKey="Kaler S" first="Stephen G." last="Kaler">Stephen G. Kaler</name><affiliation><nlm:aff id="aff13">Unit on Human Copper Metabolism, Molecular Medicine Program, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA</nlm:aff></affiliation></author><author><name sortKey="G Rtner, Jutta" sort="G Rtner, Jutta" uniqKey="G Rtner J" first="Jutta" last="G Rtner">Jutta G Rtner</name><affiliation><nlm:aff id="aff1">Department of Pediatrics and Pediatric Neurology, Georg August University, 37075 Göttingen, Germany</nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Human Genetics</title><idno type="ISSN">0002-9297</idno><idno type="eISSN">1537-6605</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Low copper and ceruloplasmin in serum are the diagnostic hallmarks for Menkes disease, Wilson disease, and aceruloplasminemia. We report on five patients from four unrelated families with these biochemical findings who presented with a lethal autosomal-recessive syndrome of congenital cataracts, hearing loss, and severe developmental delay. Cerebral MRI showed pronounced cerebellar hypoplasia and hypomyelination. Homozygosity mapping was performed and displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous or compound heterozygous mutations for all affected subjects in <italic>SLC33A1</italic> encoding a highly conserved acetylCoA transporter (AT-1) required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization of the protein. We also showed that AT-1 knockdown in HepG2 cells leads to reduced ceruloplasmin secretion, indicating that the low copper in serum is due to reduced ceruloplasmin levels and is not a sign of copper deficiency. The severity of the phenotype implies an essential role of AT-1 in proper posttranslational modification of numerous proteins, without which normal lens and brain development is interrupted. Furthermore, AT-1 defects are a new and important differential diagnosis in patients with low copper and ceruloplasmin in serum.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-title-group><journal-title>American Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22243965</article-id><article-id pub-id-type="pmc">3257879</article-id><article-id pub-id-type="publisher-id">AJHG1037</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2011.11.030</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Mutations in <italic>SLC33A1</italic> Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Huppke</surname><given-names>Peter</given-names></name><email>phuppke@med.uni-goettingen.de</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">14</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>Brendel</surname><given-names>Cornelia</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">14</xref></contrib><contrib contrib-type="author"><name><surname>Kalscheuer</surname><given-names>Vera</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Korenke</surname><given-names>Georg Christoph</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Marquardt</surname><given-names>Iris</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Freisinger</surname><given-names>Peter</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Christodoulou</surname><given-names>John</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Hillebrand</surname><given-names>Merle</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Pitelet</surname><given-names>Gaele</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Wilson</surname><given-names>Callum</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Gruber-Sedlmayr</surname><given-names>Ursula</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Ullmann</surname><given-names>Reinhard</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Haas</surname><given-names>Stefan</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Elpeleg</surname><given-names>Orly</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Nürnberg</surname><given-names>Gudrun</given-names></name><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Nürnberg</surname><given-names>Peter</given-names></name><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Dad</surname><given-names>Shzeena</given-names></name><xref rid="aff12" ref-type="aff">12</xref></contrib><contrib contrib-type="author"><name><surname>Møller</surname><given-names>Lisbeth Birk</given-names></name><xref rid="aff12" ref-type="aff">12</xref></contrib><contrib contrib-type="author"><name><surname>Kaler</surname><given-names>Stephen G.</given-names></name><xref rid="aff13" ref-type="aff">13</xref></contrib><contrib contrib-type="author"><name><surname>Gärtner</surname><given-names>Jutta</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Department of Pediatrics and Pediatric Neurology, Georg August University, 37075 Göttingen, Germany</aff><aff id="aff2"><label>2</label>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</aff><aff id="aff3"><label>3</label>Department of Neuropediatrics, Children's Hospital, 26133 Oldenburg, Germany</aff><aff id="aff4"><label>4</label>Department of Pediatrics, Klinikum am Steinenberg, 72764 Reutlingen, Germany</aff><aff id="aff5"><label>5</label>Western Sydney Genetics Program, The Children's Hospital at Westmead, and Disciplines of Paediatrics and Child Health and Genetic Medicine, Sydney Medical School, University of Sydney, 2145 Westmead, Australia</aff><aff id="aff6"><label>6</label>Service de Neuropédiatrie, CHU Nice, 6200 Nice, France</aff><aff id="aff7"><label>7</label>National Metabolic Service, Starship Children's Hospital, 1142 Auckland, New Zealand</aff><aff id="aff8"><label>8</label>Department of Pediatrics, Medical University of Graz, 8010 Graz, Austria</aff><aff id="aff9"><label>9</label>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</aff><aff id="aff10"><label>10</label>Monique and Jacques Roboh Department of Genetic Research, Department of Genetic and Metabolic Diseases, Hadassah, Hebrew University Medical Center, 91050 Jerusalem, Israel</aff><aff id="aff11"><label>11</label>Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany</aff><aff id="aff12"><label>12</label>Department for Applied Human Molecular Genetics Kennedy Center, 2600 Glostrup, Denmark</aff><aff id="aff13"><label>13</label>Unit on Human Copper Metabolism, Molecular Medicine Program, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>phuppke@med.uni-goettingen.de</email></corresp><fn id="fn1"><label>14</label><p>These authors contributed equally to this work</p></fn></author-notes><pub-date pub-type="ppub"><day>13</day><month>1</month><year>2012</year></pub-date><volume>90</volume><issue>1</issue><fpage>61</fpage><lpage>68</lpage><history><date date-type="received"><day>20</day><month>9</month><year>2011</year></date><date date-type="rev-recd"><day>20</day><month>10</month><year>2011</year></date><date date-type="accepted"><day>30</day><month>11</month><year>2011</year></date></history><permissions><copyright-statement>© 2012 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement><copyright-year>2012</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder></permissions><abstract><p>Low copper and ceruloplasmin in serum are the diagnostic hallmarks for Menkes disease, Wilson disease, and aceruloplasminemia. We report on five patients from four unrelated families with these biochemical findings who presented with a lethal autosomal-recessive syndrome of congenital cataracts, hearing loss, and severe developmental delay. Cerebral MRI showed pronounced cerebellar hypoplasia and hypomyelination. Homozygosity mapping was performed and displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous or compound heterozygous mutations for all affected subjects in <italic>SLC33A1</italic> encoding a highly conserved acetylCoA transporter (AT-1) required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization of the protein. We also showed that AT-1 knockdown in HepG2 cells leads to reduced ceruloplasmin secretion, indicating that the low copper in serum is due to reduced ceruloplasmin levels and is not a sign of copper deficiency. The severity of the phenotype implies an essential role of AT-1 in proper posttranslational modification of numerous proteins, without which normal lens and brain development is interrupted. Furthermore, AT-1 defects are a new and important differential diagnosis in patients with low copper and ceruloplasmin in serum.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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