Identification and Characterization of an Inborn Error of Metabolism Caused by Dihydrofolate Reductase Deficiency

被引：66

作者：

Banka, Siddharth ^{[1
]}

Blom, Henk J. ^{[2
]}

Walter, John ^{[1
]}

Aziz, Majid ^{[3
]}

Urquhart, Jill ^{[1
]}

Clouthier, Christopher M. ^{[4
,5
]}

Rice, Gillian I. ^{[1
]}

de Brouwer, Arjan P. M. ^{[6
]}

Hilton, Emma ^{[1
]}

Vassallo, Grace ^{[3
]}

Will, Andrew ^{[7
]}

Smith, Desiree E. C. ^{[2
]}

Smulders, Yvo M. ^{[8
]}

Wevers, Ron A. ^{[9
]}

Steinfeld, Robert ^{[10
]}

Heales, Simon ^{[11
,12
]}

Crow, Yanick J. ^{[1
]}

Pelletier, Joelle N. ^{[4
,5
]}

Jones, Simon ^{[1
]}

Newman, William G. ^{[1
]}

机构：

[1] Univ Manchester, MAHSC, St Marys Hosp, Manchester M13 9WL, Lancs, England

[2] Vrije Univ Amsterdam, Metab Unit, Dept Clin Chem, Inst Cardiovasc Res,Med Ctr Amsterdam, NL-1081 HV Amsterdam, Netherlands

[3] Cent Manchester Univ Hosp NHS Fdn Trust, MAHSC, St Marys Hosp, Manchester M13 9WL, Lancs, England

[4] Univ Montreal, Dept Biochim, Montreal, PQ H3C 3J7, Canada

[5] Univ Montreal, Dept Chim, Montreal, PQ H3C 3J7, Canada

[6] Radboud Univ Nijmegen, Dept Human Genet, Inst Genet & Metab Dis, Med Ctr, NL-6525 GA Nijmegen, Netherlands

[7] Cent Manchester Fdn NHS Trust, MAHSC, St Marys Hosp, Manchester M13 9WL, Lancs, England

[8] Vrije Univ Amsterdam, Dept Internal Med, Inst Cardiovasc Res, Med Ctr Amsterdam, NL-1081 HV Amsterdam, Netherlands

[9] Radboud Univ Nijmegen, Lab Genet Endocrine & Metab Dis, Dept Lab Med, Med Ctr, NL-6525 GA Nijmegen, Netherlands

[10] Univ Gottingen, Dept Pediat, D-37075 Gottingen, Germany

[11] Great Ormond St Hosp Sick Children, Neurometab Unit, Natl Hosp, Clin & Mol Genet Unit,UCL Inst Child Hlth & Enzym, London WC1N 3JH, England

[12] Great Ormond St Hosp Sick Children, Metab Unit, London WC1N 3JH, England

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2011年 / 88卷 / 02期

基金：

加拿大自然科学与工程研究理事会;

关键词：

FOLATE METABOLISM; DIHYDROPTERIDINE REDUCTASE; ACQUIRED-RESISTANCE; METHOTREXATE; TETRAHYDROBIOPTERIN; RISK; BIOSYNTHESIS; FAMILIES; LEUKEMIA; GENES;

D O I：

10.1016/j.ajhg.2011.01.004

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 germline 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.

引用

页码：216 / 225

页数：10

共 34 条

[1] 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels - Effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling [J].