Wu Chen-Chi, Chiu Yu-Hsun, Chen Pei-Jer, Hsu Chuan-Jen
Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.
Ear Hear. 2007 Jun;28(3):332-42. doi: 10.1097/AUD.0b013e318047941e.
The m.1555A>G mutation in the mitochondria 12S rRNA gene has been reported to be an important cause of nonsyndromic hereditary hearing loss. However, remarkable interfamilial and intrafamilial variations in the phenotypes of the mutation preclude precise prognosis during genetic counseling. Hence, this study was performed to explore the factors that might contribute to the differences in the phenotypes, including aminoglycoside exposure, mutation load and mitochondrial DNA (mtDNA) background. Also reported were the prevalence and the clinical features of the m.1555A>G mutation in the hearing-impaired Taiwanese patients.
Mutations in the 12S rRNA gene were screened in a panel of 315 unrelated Taiwanese families with idiopathic sensorineural hearing loss. The clinical features in families with m.1555A>G mutation were analyzed, and the roles of aminoglycoside exposure, mutation load and mtDNA background in disease expression were investigated. Penetrance was then compared among families with different mtDNA backgrounds.
The m.1555A>G mutation was identified in a total of 10 (3.2%) families, and was characterized clinically by progressive, postlingual and bilaterally symmetric sensorineural hearing loss and normal temporal bone radiological results. The m.1555A>G mutation was homoplasmic (i.e., all the mitochondrial DNA carries the mutation) in all the matrilineal relatives in these 10 pedigrees. Among the 44 hearing-impaired relatives of the 10 pedigrees, only two recalled definite episodes of aminoglycoside-induced hearing loss. mtDNA backgrounds in these 10 families could be categorized into 6 main haplogroups (A, B, D, F, M7, N*), including three families belonging to haplogroup F, two belonging to haplogroup A, two belonging to haplogroup M7, and three belonging to haplogroups B, N* and D, respectively. Penetrance differed among various haplogroups, and certain haplogroups appeared to be associated with a lower penetrance, like the three haplogroup F families, in which the penetrance ranged from 13 to 33%. Further analysis confirmed a heterogeneous distribution of hearing-impaired subjects among various haplogroups (Chi-square test, p = 0.018).
The mitochondrial m.1555A>G mutation accounted for 3.2% of the Taiwanese families (0% of the simplex families and 11% of multiplex families respectively) with sensorineural hearing impairment of unknown etiology. Since it was identified in a variety of mtDNA backgrounds, the mutation appeared to arise from multiple origins in Taiwanese. As subjects with various haplogroups demonstrated different penetrance, mtDNA background might exert effects on the disease expression of the m.1555A>G mutation.
线粒体12S rRNA基因中的m.1555A>G突变据报道是导致非综合征性遗传性听力损失的一个重要原因。然而，该突变表型在家族间和家族内存在显著差异，这使得遗传咨询期间难以进行精确的预后判断。因此，本研究旨在探索可能导致表型差异的因素，包括氨基糖苷类药物暴露、突变负荷和线粒体DNA（mtDNA）背景。同时还报道了台湾听力受损患者中m.1555A>G突变的患病率及临床特征。
对315个患有特发性感音神经性听力损失的非相关台湾家庭进行12S rRNA基因突变筛查。分析携带m.1555A>G突变的家庭的临床特征，并研究氨基糖苷类药物暴露、突变负荷和mtDNA背景在疾病表达中的作用。然后比较不同mtDNA背景的家庭之间的外显率。
共在10个（3.2%）家庭中鉴定出m.1555A>G突变，其临床特征为进行性、语后起病且双侧对称的感音神经性听力损失，颞骨放射学结果正常。在这10个家系的所有母系亲属中，m.1555A>G突变均为纯质的（即所有线粒体DNA均携带该突变）。在这10个家系的44名听力受损亲属中，只有两人回忆起明确的氨基糖苷类药物所致听力损失发作。这10个家庭的mtDNA背景可分为6个主要单倍群（A、B、D、F、M7、N*），其中3个家庭属于单倍群F，2个属于单倍群A，2个属于单倍群M7，3个分别属于单倍群B、N*和D。不同单倍群的外显率不同，某些单倍群似乎与较低的外显率相关，如3个单倍群F家庭，其外显率在13%至33%之间。进一步分析证实，听力受损个体在不同单倍群中的分布存在异质性（卡方检验，p = 0.018）。
线粒体m.1555A>G突变在台湾病因不明的感音神经性听力障碍家庭中占3.2%（分别在散发病例家庭中占0%，在多个病例家庭中占11%）。由于在多种mtDNA背景中均鉴定出该突变，该突变在台湾似乎起源于多个源头。由于不同单倍群的个体表现出不同的外显率，mtDNA背景可能对m.1555A>G突变的疾病表达产生影响。
