Department of Otolaryngology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai 200031, China.
J Genet Genomics. 2011 Dec 20;38(12):585-91. doi: 10.1016/j.jgg.2011.11.003. Epub 2011 Nov 22.
Waardenburg syndrome type II (WS2) is associated with syndromic deafness. A subset of WS2, WS2A, accounting for approximately 15% of patients, is attributed to mutations in the microphthalmia-associated transcription factor (MITF) gene. We examined the genetic basis of WS2 in a large Chinese family. All 9 exons of the MITF gene, the single coding exon (exon 2) of the most common hereditary deafness gene GJB2 and the mitochondrial DNA (mtDNA) 12S rRNA were sequenced. A novel heterozygous mutation c.[742_743delAAinsT;746_747delCA] in exon 8 of the MITF gene co-segregates with WS2 in the family. The MITF mutation results in a premature termination codon and a truncated MITF protein with only 247 of the 419 wild type amino acids. The deaf proband had this MITF gene heterozygous mutation as well as a c.[109G>A]+[235delC] compound heterozygous pathogenic mutation in the GJB2 gene. No pathogenic mutation was found in mtDNA 12S rRNA in this family. Thus, a novel compound heterozygous mutation, c.[742_743delAAinsT;746_747delCA] in MITF exon 8 was the key genetic reason for WS2 in this family, and a digenic effect of MITF and GJB2 genes may contribute to deafness of the proband.
瓦登伯格综合征 II 型（WS2）与综合征性耳聋有关。WS2 的一个亚组，WS2A，约占患者的 15%，归因于小眼相关转录因子（MITF）基因的突变。我们在一个大型中国家庭中研究了 WS2 的遗传基础。MITF 基因的所有 9 个外显子、最常见遗传性耳聋基因 GJB2 的单一编码外显子（外显子 2）和线粒体 DNA（mtDNA）12S rRNA 均进行了测序。MITF 基因外显子 8 中的一个新的杂合突变 c.[742_743delAAinsT;746_747delCA]与该家族中的 WS2 共分离。MITF 突变导致提前终止密码子和截断的 MITF 蛋白，只有野生型 419 个氨基酸中的 247 个。耳聋先证者既有 MITF 基因杂合突变，又有 GJB2 基因 c.[109G>A]+[235delC]复合杂合致病性突变。该家族的 mtDNA 12S rRNA 中未发现致病性突变。因此，MITF 外显子 8 中的新型复合杂合突变 c.[742_743delAAinsT;746_747delCA]是该家族 WS2 的关键遗传原因，MITF 和 GJB2 基因的双基因效应可能导致先证者耳聋。
