Diversity of cystathionine beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion.
Diversity of cystathionine beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion.
复制标题
具有最常见同型半胱氨酸尿症突变 c.833T>C 的胱硫醚β-合酶单倍型的多样性：基因转换的可能作用。
DOI：
10.1002/humu.20430
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发表时间：
2007
期刊：
影响因子：
3.9
通讯作者：
Wilcken,Br
中科院分区：
文献类型：
--
作者：
Vyletal,Petr;Sokolová,Jitka;Cooper,DavidN;Kraus,JanP;Krawczak,Michael;Pepe,Guglielmina;Rickards,Olga;Koch,HansG;Linnebank,Michael;Kluijtmans,LeoAJ;Blom,HenkJ;Boers,GodfriedHJ;Gaustadnes,Mette;Skovby,Flemming;Wilcken,Br
Cbs基因c.833T和gt；C转换(p.I278 T)的纯合性或复合杂合性是西欧人吡哆醇反应性同型半胱氨酸尿症的最常见原因。然而，在几个欧洲国家的健康新生儿中观察到的致病性c.833C等位基因的频率(qc.833C≊3.3x10-3)，根据观察到的有症状的同型半胱氨酸尿症患者的数量(qc.833C∼0.18×10-3)，比预期的高20倍，这意味着临床上不能确定。有趣的是，在世界各地的非同型半胱氨酸尿症患者的相当大比例的染色体中，c.833C突变还伴随着一个68bp的插入c.[833C；844_845ins68]。我们试图研究致病的和非致病的c.[833C；−]染色体之间的关系，并确定致病的c.[833C；C833C]染色体是相同的，还是由反复突变引起的。对随机选择的780条捷克和撒哈拉以南非洲野生型染色体的初步单倍型分析，利用12个基因内标记，发现29个不同的CBShaplotype，其中10个携带c.[833C；844_845ins68]组合；没有一个携带单独的c.833C或c.844_845ins68突变。随后对69条致病c.[833C；−]染色体的检查发现，由于c.833C的存在，三种不相关的单倍型与野生型不同，这三种不相关的单倍型由于c.833C的存在而在过去反复且独立地发生过c.833T>；C转换。由于c.833T不在一个明显的突变热点内，我们推测这三条致病且相对流行的c.[833C；−]染色体可能是以常见的非致病c.[833C；844_845ins68]染色体为模板，通过反复基因转化而产生的。Hum Mutat 28(3)，255-264,2007。2006年出版，Wiley-Liss，Inc.
Homozygosity or compound heterozygosity for the c.833T>C transition (p.I278 T) in the cystathionine beta‐synthase (CBS) gene represents the most common cause of pyridoxine‐responsive homocystinuria in Western Eurasians. However, the frequency of the pathogenic c.833C allele, as observed in healthy newborns from several European countries (qc.833C≊ 3.3 × 10–3), is ∼20‐fold higher than expected on the basis of the observed number of symptomatic homocystinuria patients carrying this mutation (qc.833C≊ 0.18 × 10–3), implying clinical underascertainment. Intriguingly, the c.833C mutation is also present in combination with a 68‐bp insertion, c.[833C; 844_845ins68], in a substantial proportion of chromosomes from nonhomocystinuric individuals worldwide. We have sought to study the relationship between the pathogenic and nonpathogenic c.833C‐bearing chromosomes and to determine whether the pathogenic c.[833C; −] chromosomes are identical‐by‐descent or instead arose by recurrent mutation. Initial haplotype analysis of 780 randomly selected Czech and sub‐Saharan African wild‐type chromosomes, employing 12 intragenic markers, revealed 29 distinctCBShaplotypes, of which 10 carried the c.[833C; 844_845ins68] combination; none carried an isolated c.833C or c.844_845ins68 mutation. Subsequent examination of 69 pathogenic c.[833C; −] chromosomes, derived from homocystinuria patients of predominantly European origin, disclosed three unrelated haplotypes that differed from their wild‐type counterparts by virtue of the presence of c.833C, thereby indicating that c.833T>C transition has occurred repeatedly and independently in the past. Since c.833T does not reside within an obvious mutational hotspot, we surmise that the three pathogenic and comparatively prevalent c.[833C; −] chromosomes may have originated by recurrent gene conversion employing the common nonpathogenic c.[833C; 844_845ins68] chromosomes as templates. Hum Mutat 28(3), 255–264, 2007. Published 2006 Wiley‐Liss, Inc.