Mutations in the dopamine β-hydroxylase gene are associated with human norepinephrine deficiency

被引:77
作者
Kim, CH
Zabetian, CP
Cubells, JF
Cho, S
Biaggioni, I
Cohen, BM
Robertson, D
Kim, KS
机构
[1] Harvard Univ, McLean Hosp, Sch Med, Mol Neurobiol Lab, Belmont, MA 02178 USA
[2] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA
[3] VA Connecticut Healthcare Syst, Dept Psychiat, West Haven, CT USA
[4] Vanderbilt Univ, Dept Pathol & Med, Autonom Dysfunct Clin & Clin Res Ctr, Nashville, TN USA
[5] Harvard Univ, McLean Hosp, Sch Med, Mol Pharmacol Lab, Belmont, MA 02178 USA
来源
AMERICAN JOURNAL OF MEDICAL GENETICS | 2002年 / 108卷 / 02期
关键词
dopamine beta-hydroxylase; norepinephrine deficiency; dopamine; splicing donor site; missense mutation; autonomic failure;
D O I
10.1002/ajmg.10196
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Norepinephrine (NE), a key neurotransmitter of the central and peripheral nervous systems, is synthesized by dopamine beta-hydroxylase (DBH) that catalyzes oxidation of dopamine (DA) to NE. NE deficiency is a congenital disorder of unknown etiology, in which affected patients suffer profound autonomic failure. Biochemical features of the syndrome include undetectable tissue and circulating levels of NE and epinephrine, elevated levels of DA, and undetectable levels of DBH. Here, we report identification of seven novel variants including four potentially pathogenic mutations in the human DBH gene (OMIM 223360) from analysis of two unrelated patients and their families. Both patients are compound heterozygotes for variants affecting expression of DBH protein. Each carries one copy of a T-->C transversion in the splice donor site of DBH intron 1, creating a premature stop codon. In patient 1, there is a missense mutation in DBH exon 2. Patient 2 carries missense mutations in exons 1 and 6 residing in cis. We propose that NE deficiency is an autosomal recessive disorder resulting from heterogeneous molecular lesions at DBH. (C) 2002 Wiley-Liss, Inc.
引用
收藏
页码:140 / 147
页数:8
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