一母系遗传非综合征耳聋大家系的临床特征和病因学研究

Clinical character and etiological study of a large family with maternally inherited non-syndromic deafness

目的探讨母系遗传非综合征型耳聋的临床特征和分子遗传机制。方法收集一遗传性耳聋大家系5代72人,详细询问病史,进行全身体格检查和听力学测试,并采集23例家系成员外周静脉血样本,采用聚合酶链式反应结合DNA直接测序法对先证者进行线粒体全基因组序列分析,发现变异后,取正常人群DNA采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)鉴定此变异是否为突变。结果此家系36例母系成员中有21例表现为不同程度的感音神经性耳聋,双耳对称,高频下降明显,发病年龄0～56岁。所有成员全身体查无异常,听力学检测无中耳疾病及蜗后病变证据。先证者mtDNA序列分析共发现23种变异,18例母系成员均携带12SrRNA基因A1555G突变,同时均携带一新的变异T1541C。A1555G和T1541C的正常人群变异频率均为0/100,余21种变异频率均大于1/100。5例父系亲属和配偶均无听力障碍,A1555G和T1541C检测阴性。结论线粒体A1555G突变是本家系耳聋的主要原因,环境因素可能参与A1555G突变表型表达的调节,T1541C为中国人群未报道新突变,可能对该家系Al555G突变所致耳聋的外显率有影响。

Objective To investigate the clinical character and molecular genetic mechanism of matrilineal non-syndromic sensorineural deafness. Methods A large family of 72 members with inherited deafness was studied. Complete history was collected, and all subjects received medical examinations and audiological evaluation. 23 peripheral blood samples were obtained from the members of the pedigree. The proband was examined for the mitochondrial genome mutation with polymerase chain reaction and DNA sequencing, while PCR-RFLP was performed to confirm the mutation. Results 21 of 36 maternal relatives exhibited symmetric bilateral sensorlneural deafness, especially hearing loss in high frequencies , with wide range of severity. The onset age ranged from 0 to 56 years old. All subjects were in good health generally. Audiologic testings displayed no middle ear or retrocochlear diseases. 23 variations were found by molecular analysis. 18 maternal relatives harbored the A1555G mitochondrial mutation in the 12SrRNA gene, also a novel variation T1541 C.Frequencies of A1555G and T1541C in controls were both 0/100, while those of the others were all more than 1/100. No heating loss and mutations were found among five spouses and paternal relatives. Conclusion The A1555 G mitochondrial mutation in the 12SrRNA gene is responsible for this disorder. Environmental determinants may play a role in the clinical expression of A 1555 G mutation. T 1541 C is a novel mutation in Chinese population, which may influence the penetrance of deafness due to A 1555 G mutation.