新MITF基因突变致先天性耳聋的遗传印迹机制研究

Hereditary deafness is complex genetic disease associated with various clinical presentations. Numerous genetic mutations in multiple genes across the genome have been reported to cause sensorineural hearing loss in a dominant manner with variable penetrance. Due to the complexity of genetic mutations in hereditary deafness, the exact mechanism is still under investigation. The lack of a comprehensive understanding of causal genetic mutations also significantly hinders the diagnosis, prognosis, and genetic consolation of the disease. To further understanding of hereditary deafness, we sequenced whole exons and partial boundary introns of 69 known deafness-causing genes in a multi-generation well-documented consanguineous Chinese family. The sequencing data revealed that a novel mutation in MITF (microphthalmia-associated transcription factor) gene, Arg341Leu, in this family. In addition to the missense mutation, the pedigree and fine-genotyping results suggest that the mutation is transmitted in a parent-of-origin specific manner. To elucidate the disease mechanism in this unique, we plan to 1) further genotype the patients and controls in this family to confirm the source of mutation, 2) compare MITF allele expressed in mRNA with the genotype of the individual, 3) elucidate the mechanism of imprinting via methylation assays, and 4) evaluate the functions of the mutated MITF protein in various cell types. The knowledge obtained in this study can potentially expand our understanding of the molecular mechanism of hereditary deafness, facilitate the early diagnosis, and establish an effective genetic analysis for disease prevention and genetic counseling for high-risk families.

先天性耳聋是临床表型复杂多样的遗传性疾病，已报道全基因组数百种基因突变可导致感音神经性耳聋并伴有不同的外显性，某些遗传性耳聋确切发病机理不清楚。本研究对一个近亲婚配三个子女都有严重耳聋的家庭做69个已知耳聋致病基因的全外显子和邻近内含子测序，发现一个新的MITF错义基因突变，Arg341Leu，表现为II型Waardenburg综合症患者为纯合突变，单纯耳聋的儿子均为杂合突变，另有7例为无耳聋的杂合突变携带者。家谱和基因型分析提示耳聋患者为父源MITF基因突变，可能与遗传印迹相关。为阐明分子发病机制，本研究组将开展：1）MITF基因突变单倍体分析；2）MITF基因表达和基因型分析；3）MITF基因甲基化研究，4）MITF基因突变功能研究。本研究具有源头创新性，将为耳聋的分子发病机理提供信息，对耳聋的早期诊断和预防，防止耳聋出生缺陷，提高我国人口素质具有重大意义。