Rothrock Caryn R, Murgia Alessandra, Sartorato Edi L, Leonardi Emanuela, Wei Sainan, Lebeis Sarah L, Yu Laura E, Elfenbein Jill L, Fisher Rachel A, Friderici Karen H
Department of Microbiology and Molecular Genetics, Michigan State University, 5163 Biomedical and Physical Sciences Building, East Lansing, Michigan 48824-4320, USA.
Hum Genet. 2003 Jul;113(1):18-23. doi: 10.1007/s00439-003-0944-2. Epub 2003 Apr 9.
Non-syndromic hearing impairment (NSHI) is the most common form of deafness and presents with no other symptoms or sensory defects. Mutations in the gap junction gene GJB2 account for a high proportion of recessive NSHI. The GJB2 gene encodes connexin 26, which forms plasma membrane channels between cochlear cells. In Caucasian populations a single mutation, 35delG, accounts for most cases of NSHI. This mutation appears to be most prevalent in individuals of Mediterranean European descent, with carrier frequencies estimated as being as high as one in thirty. The 35delG region may be a mutational hotspot. The mutation arises from the deletion of a guanine from a six-guanine stretch and nearby microsatellite markers show little evidence for linkage disequilibrium. We believe that 35delG is an old mutation in a chromosomal region of high recombination. The genetic context of the 35delG mutation was examined to distinguish between an old or a recurring mutation. We identified two single-nucleotide polymorphisms (SNPs) immediately upstream of the first exon of GJB2. Polymerase chain reaction/restriction fragment length polymorphism analysis determined the SNP genotype of 35delG containing chromosomes from various populations, including Italy, Brazil, and North America. We found the same, relatively rare, polymorphism associated with the 35delG mutation in all populations studied. We have also examined microsatellite markers D13S175, which is 80 kb telomeric to GJB2, and D13S1316, which is 80 kb centromeric to GJB2. D13S175 appears to be in weak linkage disequilibrium with 35delG, while D13S1316 is less so. SNPs located between the 35delG mutation and the microsatellite markers show strong evidence of linkage disequilibrium. Taken together, these results indicate there has been substantial recombination near the 35delG mutation; however, we present evidence that the 35delG mutation arose in European and Middle Eastern populations from a single mutational event on a founder chromosome.
非综合征性听力损失（NSHI）是最常见的耳聋形式，且不伴有其他症状或感觉缺陷。缝隙连接基因GJB2中的突变在隐性NSHI中占很大比例。GJB2基因编码连接蛋白26，其在耳蜗细胞之间形成质膜通道。在白种人群体中，单一突变35delG导致了大多数NSHI病例。这种突变在地中海欧洲血统的个体中似乎最为普遍，携带者频率估计高达三十分之一。35delG区域可能是一个突变热点。该突变源于六个鸟嘌呤序列中一个鸟嘌呤的缺失，附近的微卫星标记几乎没有显示出连锁不平衡的证据。我们认为35delG是高重组染色体区域中的一个古老突变。研究了35delG突变的遗传背景，以区分是古老突变还是反复出现的突变。我们在GJB2第一个外显子的紧邻上游鉴定出两个单核苷酸多态性（SNP）。聚合酶链反应/限制性片段长度多态性分析确定了来自包括意大利、巴西和北美的不同群体中含有35delG染色体的SNP基因型。我们发现在所有研究的群体中，与35delG突变相关的是相同的、相对罕见的多态性。我们还研究了微卫星标记D13S175（位于GJB2端粒方向80 kb处）和D13S1316（位于GJB2着丝粒方向80 kb处）。D13S175似乎与35delG存在弱连锁不平衡，而D13S1316的连锁不平衡程度较小。位于35delG突变和微卫星标记之间的SNP显示出强烈的连锁不平衡证据。综上所述，这些结果表明在35delG突变附近发生了大量重组；然而，我们提供的证据表明，35delG突变在欧洲和中东人群中源自一条奠基者染色体上的单一突变事件。
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