Dodé C, Dürr A, Pêcheux C, Mouret J F, Belal S, Bachner L, Agid Y, Kaplan J C, Brice A, Feingold J
Laboratoire de Biochimie Génétique, hôpital Cochin, Paris, France.
C R Acad Sci III. 1993 Nov;316(11):1374-80.
The molecular defect causing Huntington's disease (HD) has been found as an expansion of CAG triplets in the 5' coding region of IT15 gene. In the 29 French families reported, the HD disease is due to the expansion of the CAG triplets region above 38 copies. The complete sequencing of 10 HD alleles PCR products allowed us to confirm that expansion is restricted to the CAG repeat region and does not extend to the adjacent CCG repeat region which is also present in the PCR product. Then, we analysed linkage disequilibrium between the molecular defect and 6 DNA markers mapping to the 4p16.3 region. The most striking finding in this study is the presence of a strong linkage disequilibrium between HD and D4S127 (PvuII), D4S95 (AccI, MboI, TaqI) located in a region of 130 kb distal to IT15 gene. Two major haplotypes, comprising D4S127 (PvuII) and D4S95 (MboI, AccI) polymorphic sites, were found in the normal population as only one was found associated with HD alleles. This result can be interpreted either as an evidence for a rather recent founder effect or as several independent mutations occuring in chromosomes bearing the same haplotype.
导致亨廷顿舞蹈病（HD）的分子缺陷已被发现是IT15基因5'编码区中CAG三联体的扩增。在报道的29个法国家庭中，HD疾病是由于CAG三联体区域扩增至38个拷贝以上所致。对10个HD等位基因PCR产物的完整测序使我们能够确认扩增仅限于CAG重复区域，并未延伸至PCR产物中也存在的相邻CCG重复区域。然后，我们分析了分子缺陷与定位到4p16.3区域的6个DNA标记之间的连锁不平衡。本研究中最显著的发现是HD与位于IT15基因远端130 kb区域的D4S127（PvuII）、D4S95（AccI、MboI、TaqI）之间存在强烈的连锁不平衡。在正常人群中发现了两种主要单倍型，包含D4S127（PvuII）和D4S95（MboI、AccI）多态性位点，而仅发现一种与HD等位基因相关。这一结果既可以解释为近期奠基者效应的证据，也可以解释为在携带相同单倍型的染色体上发生的几个独立突变。
