Identification and Characterization of an Inborn Error of Metabolism Caused by Dihydrofolate Reductase Deficiency
Identifieur interne : 000919 ( PascalFrancis/Curation ); précédent : 000918; suivant : 000920Identification and Characterization of an Inborn Error of Metabolism Caused by Dihydrofolate Reductase Deficiency
Auteurs : Siddharth Banka [Royaume-Uni] ; Henk J. Blom [Pays-Bas] ; John Walter [Royaume-Uni] ; Majid Aziz [Royaume-Uni] ; Jill Urquhart [Royaume-Uni] ; Christopher M. Clouthier [Canada] ; Gillian I. Rice [Royaume-Uni] ; Arjan P. M. De Brouwer [Pays-Bas] ; Emma Hilton [Royaume-Uni] ; Grace Vassallo [Royaume-Uni] ; Andrew Will [Royaume-Uni] ; Desirée E. C. Smith [Pays-Bas] ; Yvo M. Smulders [Pays-Bas] ; Ron A. Wevers [Pays-Bas] ; Robert Steinfeld [Allemagne] ; Simon Heales [Royaume-Uni] ; Yanick J. Crow [Royaume-Uni] ; Joelle N. Pelletier [Canada] ; Simon Jones [Royaume-Uni] ; William G. Newman [Royaume-Uni]Source :
- American journal of human genetics [ 0002-9297 ] ; 2011.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Déficit, Maladie congénitale, Génétique, Homme.
English descriptors
- KwdEn :
Abstract
Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism and an important target of antineoplastic, antimicrobial, and antiinflammatory drugs. We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germ-line missense mutation in DHFR, resulting in profound enzyme deficiency. We show that cerebral folate levels, anemia, and pancytopenia of DHFR deficiency can be corrected by treatment with folinic acid. The characterization of this disorder provides evidence for the link between DHFR and metabolism of cerebral tetrahydrobiopterin, which is required for the formation of dopamine, serotonin, and norepinephrine and for the hydroxylation of aromatic amino acids. Moreover, this relationship provides insight into the role of folates in neurological conditions, including depression, Alzheimer disease, and Parkinson disease.
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">Identification and Characterization of an Inborn Error of Metabolism Caused by Dihydrofolate Reductase Deficiency</title><author><name sortKey="Banka, Siddharth" sort="Banka, Siddharth" uniqKey="Banka S" first="Siddharth" last="Banka">Siddharth Banka</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Blom, Henk J" sort="Blom, Henk J" uniqKey="Blom H" first="Henk J." last="Blom">Henk J. Blom</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Metabolic Unit, Department of Clinical Chemistry, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, De Boelelaan 1117</s1><s2>1081 HV Amsterdam</s2><s3>NLD</s3><sZ>2 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Walter, John" sort="Walter, John" uniqKey="Walter J" first="John" last="Walter">John Walter</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Aziz, Majid" sort="Aziz, Majid" uniqKey="Aziz M" first="Majid" last="Aziz">Majid Aziz</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Paediatric Neurology, MAHSC, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>4 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Urquhart, Jill" sort="Urquhart, Jill" uniqKey="Urquhart J" first="Jill" last="Urquhart">Jill Urquhart</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Clouthier, Christopher M" sort="Clouthier, Christopher M" uniqKey="Clouthier C" first="Christopher M." last="Clouthier">Christopher M. Clouthier</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Département de Biochimie and Département de Chimie, Université de Montréal</s1><s2>Montreal, Quebec H3C 3J7</s2><s3>CAN</s3><sZ>6 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Rice, Gillian I" sort="Rice, Gillian I" uniqKey="Rice G" first="Gillian I." last="Rice">Gillian I. Rice</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="De Brouwer, Arjan P M" sort="De Brouwer, Arjan P M" uniqKey="De Brouwer A" first="Arjan P. M." last="De Brouwer">Arjan P. M. De Brouwer</name><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10</s1><s2>6525 GA Nijmegen</s2><s3>NLD</s3><sZ>8 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Hilton, Emma" sort="Hilton, Emma" uniqKey="Hilton E" first="Emma" last="Hilton">Emma Hilton</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Vassallo, Grace" sort="Vassallo, Grace" uniqKey="Vassallo G" first="Grace" last="Vassallo">Grace Vassallo</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Paediatric Neurology, MAHSC, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>4 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Will, Andrew" sort="Will, Andrew" uniqKey="Will A" first="Andrew" last="Will">Andrew Will</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Paediatric Haematology, MAHSC, St. Mary's Hospital, Central Manchester Foundation NHS Trust</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>11 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Smith, Desiree E C" sort="Smith, Desiree E C" uniqKey="Smith D" first="Desirée E. C." last="Smith">Desirée E. C. Smith</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Metabolic Unit, Department of Clinical Chemistry, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, De Boelelaan 1117</s1><s2>1081 HV Amsterdam</s2><s3>NLD</s3><sZ>2 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Smulders, Yvo M" sort="Smulders, Yvo M" uniqKey="Smulders Y" first="Yvo M." last="Smulders">Yvo M. Smulders</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Department of Internal Medicine, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, De Boelelaan 1117</s1><s2>1081 HV Amsterdam</s2><s3>NLD</s3><sZ>13 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Wevers, Ron A" sort="Wevers, Ron A" uniqKey="Wevers R" first="Ron A." last="Wevers">Ron A. Wevers</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Laboratory of Genetic Endocrine and Metabolic Diseases, Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10</s1><s2>6525 GA Nijmegen</s2><s3>NLD</s3><sZ>14 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Steinfeld, Robert" sort="Steinfeld, Robert" uniqKey="Steinfeld R" first="Robert" last="Steinfeld">Robert Steinfeld</name><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Department of Pediatrics, University of Goettingen, Robert-Koch-Str. 40</s1><s2>37075 Goettingen</s2><s3>DEU</s3><sZ>15 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Heales, Simon" sort="Heales, Simon" uniqKey="Heales S" first="Simon" last="Heales">Simon Heales</name><affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Neurometabolic Unit, National Hospital, Queen Square, Clinical and Molecular Genetics Unit, UCL Institute of Child Health & Enzyme and Metabolic Unit, Great Ormond Street Hospital</s1><s2>London WC1N 3JH</s2><s3>GBR</s3><sZ>16 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Crow, Yanick J" sort="Crow, Yanick J" uniqKey="Crow Y" first="Yanick J." last="Crow">Yanick J. Crow</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Pelletier, Joelle N" sort="Pelletier, Joelle N" uniqKey="Pelletier J" first="Joelle N." last="Pelletier">Joelle N. Pelletier</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Département de Biochimie and Département de Chimie, Université de Montréal</s1><s2>Montreal, Quebec H3C 3J7</s2><s3>CAN</s3><sZ>6 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Jones, Simon" sort="Jones, Simon" uniqKey="Jones S" first="Simon" last="Jones">Simon Jones</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Newman, William G" sort="Newman, William G" uniqKey="Newman W" first="William G." last="Newman">William G. Newman</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">11-0120473</idno><date when="2011">2011</date><idno type="stanalyst">PASCAL 11-0120473 INIST</idno><idno type="RBID">Pascal:11-0120473</idno><idno type="wicri:Area/PascalFrancis/Corpus">000344</idno><idno type="wicri:Area/PascalFrancis/Curation">000919</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Identification and Characterization of an Inborn Error of Metabolism Caused by Dihydrofolate Reductase Deficiency</title><author><name sortKey="Banka, Siddharth" sort="Banka, Siddharth" uniqKey="Banka S" first="Siddharth" last="Banka">Siddharth Banka</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Blom, Henk J" sort="Blom, Henk J" uniqKey="Blom H" first="Henk J." last="Blom">Henk J. Blom</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Metabolic Unit, Department of Clinical Chemistry, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, De Boelelaan 1117</s1><s2>1081 HV Amsterdam</s2><s3>NLD</s3><sZ>2 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Walter, John" sort="Walter, John" uniqKey="Walter J" first="John" last="Walter">John Walter</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Aziz, Majid" sort="Aziz, Majid" uniqKey="Aziz M" first="Majid" last="Aziz">Majid Aziz</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Paediatric Neurology, MAHSC, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>4 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Urquhart, Jill" sort="Urquhart, Jill" uniqKey="Urquhart J" first="Jill" last="Urquhart">Jill Urquhart</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Clouthier, Christopher M" sort="Clouthier, Christopher M" uniqKey="Clouthier C" first="Christopher M." last="Clouthier">Christopher M. Clouthier</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Département de Biochimie and Département de Chimie, Université de Montréal</s1><s2>Montreal, Quebec H3C 3J7</s2><s3>CAN</s3><sZ>6 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Rice, Gillian I" sort="Rice, Gillian I" uniqKey="Rice G" first="Gillian I." last="Rice">Gillian I. Rice</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="De Brouwer, Arjan P M" sort="De Brouwer, Arjan P M" uniqKey="De Brouwer A" first="Arjan P. M." last="De Brouwer">Arjan P. M. De Brouwer</name><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10</s1><s2>6525 GA Nijmegen</s2><s3>NLD</s3><sZ>8 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Hilton, Emma" sort="Hilton, Emma" uniqKey="Hilton E" first="Emma" last="Hilton">Emma Hilton</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Vassallo, Grace" sort="Vassallo, Grace" uniqKey="Vassallo G" first="Grace" last="Vassallo">Grace Vassallo</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Paediatric Neurology, MAHSC, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>4 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Will, Andrew" sort="Will, Andrew" uniqKey="Will A" first="Andrew" last="Will">Andrew Will</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Paediatric Haematology, MAHSC, St. Mary's Hospital, Central Manchester Foundation NHS Trust</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>11 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Smith, Desiree E C" sort="Smith, Desiree E C" uniqKey="Smith D" first="Desirée E. C." last="Smith">Desirée E. C. Smith</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Metabolic Unit, Department of Clinical Chemistry, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, De Boelelaan 1117</s1><s2>1081 HV Amsterdam</s2><s3>NLD</s3><sZ>2 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Smulders, Yvo M" sort="Smulders, Yvo M" uniqKey="Smulders Y" first="Yvo M." last="Smulders">Yvo M. Smulders</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Department of Internal Medicine, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, De Boelelaan 1117</s1><s2>1081 HV Amsterdam</s2><s3>NLD</s3><sZ>13 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Wevers, Ron A" sort="Wevers, Ron A" uniqKey="Wevers R" first="Ron A." last="Wevers">Ron A. Wevers</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Laboratory of Genetic Endocrine and Metabolic Diseases, Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10</s1><s2>6525 GA Nijmegen</s2><s3>NLD</s3><sZ>14 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Steinfeld, Robert" sort="Steinfeld, Robert" uniqKey="Steinfeld R" first="Robert" last="Steinfeld">Robert Steinfeld</name><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Department of Pediatrics, University of Goettingen, Robert-Koch-Str. 40</s1><s2>37075 Goettingen</s2><s3>DEU</s3><sZ>15 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Heales, Simon" sort="Heales, Simon" uniqKey="Heales S" first="Simon" last="Heales">Simon Heales</name><affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Neurometabolic Unit, National Hospital, Queen Square, Clinical and Molecular Genetics Unit, UCL Institute of Child Health & Enzyme and Metabolic Unit, Great Ormond Street Hospital</s1><s2>London WC1N 3JH</s2><s3>GBR</s3><sZ>16 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Crow, Yanick J" sort="Crow, Yanick J" uniqKey="Crow Y" first="Yanick J." last="Crow">Yanick J. Crow</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Pelletier, Joelle N" sort="Pelletier, Joelle N" uniqKey="Pelletier J" first="Joelle N." last="Pelletier">Joelle N. Pelletier</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Département de Biochimie and Département de Chimie, Université de Montréal</s1><s2>Montreal, Quebec H3C 3J7</s2><s3>CAN</s3><sZ>6 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Jones, Simon" sort="Jones, Simon" uniqKey="Jones S" first="Simon" last="Jones">Simon Jones</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Newman, William G" sort="Newman, William G" uniqKey="Newman W" first="William G." last="Newman">William G. Newman</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author></analytic><series><title level="j" type="main">American journal of human genetics</title><title level="j" type="abbreviated">Am. j. hum. genet.</title><idno type="ISSN">0002-9297</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">American journal of human genetics</title><title level="j" type="abbreviated">Am. j. hum. genet.</title><idno type="ISSN">0002-9297</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Characterization</term><term>Congenital disease</term><term>Deficiency</term><term>Dihydrofolate reductase</term><term>Enzymopathy</term><term>Genetics</term><term>Human</term><term>Identification</term><term>Metabolic diseases</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Maladie métabolique</term><term>Déficit</term><term>Identification</term><term>Caractérisation</term><term>Maladie congénitale</term><term>Enzymopathie</term><term>Dihydrofolate reductase</term><term>Génétique</term><term>Homme</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Déficit</term><term>Maladie congénitale</term><term>Génétique</term><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism and an important target of antineoplastic, antimicrobial, and antiinflammatory drugs. We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germ-line missense mutation in DHFR, resulting in profound enzyme deficiency. We show that cerebral folate levels, anemia, and pancytopenia of DHFR deficiency can be corrected by treatment with folinic acid. The characterization of this disorder provides evidence for the link between DHFR and metabolism of cerebral tetrahydrobiopterin, which is required for the formation of dopamine, serotonin, and norepinephrine and for the hydroxylation of aromatic amino acids. Moreover, this relationship provides insight into the role of folates in neurological conditions, including depression, Alzheimer disease, and Parkinson disease.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0002-9297</s0></fA01><fA02 i1="01"><s0>AJHGAG</s0></fA02><fA03 i2="1"><s0>Am. j. hum. genet.</s0></fA03><fA05><s2>88</s2></fA05><fA06><s2>2</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Identification and Characterization of an Inborn Error of Metabolism Caused by Dihydrofolate Reductase Deficiency</s1></fA08><fA11 i1="01" i2="1"><s1>BANKA (Siddharth)</s1></fA11><fA11 i1="02" i2="1"><s1>BLOM (Henk J.)</s1></fA11><fA11 i1="03" i2="1"><s1>WALTER (John)</s1></fA11><fA11 i1="04" i2="1"><s1>AZIZ (Majid)</s1></fA11><fA11 i1="05" i2="1"><s1>URQUHART (Jill)</s1></fA11><fA11 i1="06" i2="1"><s1>CLOUTHIER (Christopher M.)</s1></fA11><fA11 i1="07" i2="1"><s1>RICE (Gillian I.)</s1></fA11><fA11 i1="08" i2="1"><s1>DE BROUWER (Arjan P. M.)</s1></fA11><fA11 i1="09" i2="1"><s1>HILTON (Emma)</s1></fA11><fA11 i1="10" i2="1"><s1>VASSALLO (Grace)</s1></fA11><fA11 i1="11" i2="1"><s1>WILL (Andrew)</s1></fA11><fA11 i1="12" i2="1"><s1>SMITH (Desirée E. C.)</s1></fA11><fA11 i1="13" i2="1"><s1>SMULDERS (Yvo M.)</s1></fA11><fA11 i1="14" i2="1"><s1>WEVERS (Ron A.)</s1></fA11><fA11 i1="15" i2="1"><s1>STEINFELD (Robert)</s1></fA11><fA11 i1="16" i2="1"><s1>HEALES (Simon)</s1></fA11><fA11 i1="17" i2="1"><s1>CROW (Yanick J.)</s1></fA11><fA11 i1="18" i2="1"><s1>PELLETIER (Joelle N.)</s1></fA11><fA11 i1="19" i2="1"><s1>JONES (Simon)</s1></fA11><fA11 i1="20" i2="1"><s1>NEWMAN (William G.)</s1></fA11><fA14 i1="01"><s1>Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>17 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></fA14><fA14 i1="02"><s1>Metabolic Unit, Department of Clinical Chemistry, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, De Boelelaan 1117</s1><s2>1081 HV Amsterdam</s2><s3>NLD</s3><sZ>2 aut.</sZ><sZ>12 aut.</sZ></fA14><fA14 i1="03"><s1>Paediatric Neurology, MAHSC, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>4 aut.</sZ><sZ>10 aut.</sZ></fA14><fA14 i1="04"><s1>Département de Biochimie and Département de Chimie, Université de Montréal</s1><s2>Montreal, Quebec H3C 3J7</s2><s3>CAN</s3><sZ>6 aut.</sZ><sZ>18 aut.</sZ></fA14><fA14 i1="05"><s1>Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10</s1><s2>6525 GA Nijmegen</s2><s3>NLD</s3><sZ>8 aut.</sZ></fA14><fA14 i1="06"><s1>Paediatric Haematology, MAHSC, St. Mary's Hospital, Central Manchester Foundation NHS Trust</s1><s2>Manchester M13 9WL</s2><s3>GBR</s3><sZ>11 aut.</sZ></fA14><fA14 i1="07"><s1>Department of Internal Medicine, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, De Boelelaan 1117</s1><s2>1081 HV Amsterdam</s2><s3>NLD</s3><sZ>13 aut.</sZ></fA14><fA14 i1="08"><s1>Laboratory of Genetic Endocrine and Metabolic Diseases, Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10</s1><s2>6525 GA Nijmegen</s2><s3>NLD</s3><sZ>14 aut.</sZ></fA14><fA14 i1="09"><s1>Department of Pediatrics, University of Goettingen, Robert-Koch-Str. 40</s1><s2>37075 Goettingen</s2><s3>DEU</s3><sZ>15 aut.</sZ></fA14><fA14 i1="10"><s1>Neurometabolic Unit, National Hospital, Queen Square, Clinical and Molecular Genetics Unit, UCL Institute of Child Health & Enzyme and Metabolic Unit, Great Ormond Street Hospital</s1><s2>London WC1N 3JH</s2><s3>GBR</s3><sZ>16 aut.</sZ></fA14><fA20><s1>216-225</s1></fA20><fA21><s1>2011</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>2610</s2><s5>354000193674660100</s5></fA43><fA44><s0>0000</s0><s1>© 2011 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>33 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>11-0120473</s0></fA47><fA60><s1>P</s1><s3>C</s3></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>American journal of human genetics</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism and an important target of antineoplastic, antimicrobial, and antiinflammatory drugs. We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germ-line missense mutation in DHFR, resulting in profound enzyme deficiency. We show that cerebral folate levels, anemia, and pancytopenia of DHFR deficiency can be corrected by treatment with folinic acid. The characterization of this disorder provides evidence for the link between DHFR and metabolism of cerebral tetrahydrobiopterin, which is required for the formation of dopamine, serotonin, and norepinephrine and for the hydroxylation of aromatic amino acids. Moreover, this relationship provides insight into the role of folates in neurological conditions, including depression, Alzheimer disease, and Parkinson disease.</s0></fC01><fC02 i1="01" i2="X"><s0>002A04</s0></fC02><fC02 i1="02" i2="X"><s0>002A07</s0></fC02><fC02 i1="03" i2="X"><s0>002B23A</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Maladie métabolique</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Metabolic diseases</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Metabolismo patología</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Déficit</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Deficiency</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Déficiencia</s0><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Identification</s0><s5>09</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Identification</s0><s5>09</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Identificación</s0><s5>09</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Caractérisation</s0><s5>10</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Characterization</s0><s5>10</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Caracterización</s0><s5>10</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Maladie congénitale</s0><s5>11</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Congenital disease</s0><s5>11</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Enfermedad congénita</s0><s5>11</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Enzymopathie</s0><s5>12</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Enzymopathy</s0><s5>12</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Enzimopatía</s0><s5>12</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Dihydrofolate reductase</s0><s2>FE</s2><s5>13</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Dihydrofolate reductase</s0><s2>FE</s2><s5>13</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Dihydrofolate reductase</s0><s2>FE</s2><s5>13</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Génétique</s0><s5>14</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Genetics</s0><s5>14</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Genética</s0><s5>14</s5></fC03><fC03 i1="09" i2="X" l="FRE"><s0>Homme</s0><s5>15</s5></fC03><fC03 i1="09" i2="X" l="ENG"><s0>Human</s0><s5>15</s5></fC03><fC03 i1="09" i2="X" l="SPA"><s0>Hombre</s0><s5>15</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Oxidoreductases</s0><s2>FE</s2></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Oxidoreductases</s0><s2>FE</s2></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Oxidoreductases</s0><s2>FE</s2></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Enzima</s0><s2>FE</s2></fC07><fN21><s1>080</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard></inist></record>Pour manipuler ce document sous Unix (Dilib)
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