Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase
Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase
复制标题
DOI：
10.1002/humu.20366
复制
发表时间：
2006-09-01
期刊：
影响因子：
3.9
通讯作者：
Blau, Nenad
中科院分区：
文献类型：
--
作者：
Thoeny, Beat;Blau, Nenad
四氢生物蝶呤 (BH4) 缺乏症是一组高度异质性的疾病，涉及数百名患者，迄今为止，在 GTP 环化水解酶 I (GTPCH)、6-丙酮酰四氢蝶呤合酶 (PTPS)、墨蝶呤还原酶 (SR)、甲醇胺-4a-脱水酶 (PCD) 或二氢蝶啶还原酶（DHPR）基因。列出并回顾了导致三种生物合成酶（GTPCH、PTPS 和 SR）之一或两种再生酶（PCD 和 DHPR）减少的突变谱。此外，还编译了当前的基因组变异或 SNP。 GCH1 的突变分散在整个基因中，据报道，104 个突变等位基因中只有 5 个以纯合状态存在，可导致与单胺神经递质缺乏相关的常染色体隐性遗传性高苯丙氨酸血症 (HPA)。 GCH1 ace 中几乎所有其他 99 个不同的突变等位基因与野生型等位基因一起观察到，并以显性方式引起多巴反应性肌张力障碍（DRD、Sekawa 病），且外显率降低。复合杂合或纯合突变遍布整个基因，PTS 有 44 个突变等位基因，PCBD 有 9 个突变等位基因，QDPR 有 29 个突变等位基因。这些突变会导致常染色体隐性遗传形式的 HPA，大多伴有神经递质多巴胺和血清素的缺乏。墨蝶呤还原酶活性缺乏是 BH4 缺陷的常染色体隐性变异，不存在 HPA，在 SPR 基因外显子 2 或 3 或内含子 2 中具有 7 个不同突变等位基因的患者中被诊断出。这里提供的所有突变的详细信息在 BIOMDB 数据库 (www.bh4.org) 中不断更新。
Tetrahydrobiopterin (BH4) deficiencies are a highly heterogeneous group of disorders with several hundred patients, and so far a total of 193 different mutant alleles or molecular lesions identified in the GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SR), carbinolamine-4a-dehydratase (PCD), or dihydropteridine reductase (DHPR) genes. The spectrum of mutations causing a reduction in one of the three biosynthetic (GTPCH, PTPS, and SR) or the two regenerating enzymes (PCD and DHPR) is tabulated and reviewed. Furthermore, current genomic variations or SNPs are also compiled. Mutations in GCH1 are scattered over the entire gene, and only 5 out of 104 mutant alleles, present in a homozygous state, are reported to cause the autosomal recessive form of inheritable hyperphenylalaninemia (HPA) associated with monoamine neurotransmitter deficiency. Almost all other 99 different mutant alleles in GCH1 ace observed together with a wild-type allele and cause Dopa-responsive dystonia (DRD, Segawa disease) in a dominant fashion with reduced penetrance. Compound heterozygous or homozygous mutations are spread over the entire genes for PTS with 44 mutant alleles, for PCBD with nine mutant alleles, and for QDPR with 29 mutant alleles. These mutations cause an autosomal recessive inherited form of HPA, mostly accompanied by a deficiency of the neurotransmitters dopamine and serotonin. Lack of sepiapterin reductase activity, an autosomal recessive variant of BH4 deficiency presenting without HPA, was diagnosed in patients with seven different mutant alleles in the SPR gene in exons 2 or 3 or in intron 2. Details on all mutations presented here are constantly updated in the BIOMDB database (www.bh4.org).