Late onset nonsyndromic hearing loss in a Dongxiang Chinese family is associated with the 593T > C variant in the mitochondrial tRNAPhe gene
Late onset nonsyndromic hearing loss in a Dongxiang Chinese family is associated with the 593T > C variant in the mitochondrial tRNAPhe gene
复制标题
中国东乡族晚发性非综合征性听力损失与线粒体 tRNA(Phe) 基因中的 593T > C 变异有关
DOI：
10.1016/j.mito.2017.05.013
复制
发表时间：
2017-07-01
期刊：
影响因子：
4.4
通讯作者：
Guan, Min-Xin
中科院分区：
文献类型：
--
作者：
Chen, Xiaowan;Nie, Zhipeng;Guan, Min-Xin
我们在这里报告了一个四代东乡族中国谱系的临床、遗传、分子和生化特征，该谱系患有暗示性母源性传播的非综合征性听力损失。 10 名母系亲属中有 5 名在感音神经性听力损失发作时表现出不同的严重程度和年龄。该家庭的母系亲属听力损失的平均发病年龄为29岁。对他们线粒体基因组的分子分析鉴定出属于亚洲单倍群 G2a2a 的 tRNA(Phe) 593T > C 变体。 m.593T > C 变体位于 DHU 环的第 17 位，该位置对于 tRNA 的结构和功能很重要。预计 m.593T > C 变体会改变 tRNA(Phe) 的结构和功能。通过使用来自中国家族的类淋巴母细胞系，我们发现突变细胞系中 tRNA(Phe) 的稳态水平降低了 46%。蛋白质印迹分析显示，携带 m.593T > C 变体的突变细胞系的线粒体翻译水平降低了 35%。线粒体翻译受损显然是呼吸能力显着降低的主要原因。呼吸缺陷降低了突变细胞系中线粒体 ATP 的产生。这些数据提供了证据，表明 m.593T > C 变体引起的线粒体功能障碍会导致迟发性非综合征性听力损失。因此，我们的研究结果可能为理解病理生理学提供新的见解，并为母系遗传性听力损失的管理和治疗提供有价值的信息。
We report here the clinical, genetic, molecular and biochemical characterization of a four-generation Dongxiang Chinese pedigree with suggestively maternally transmitted non-syndromic hearing loss. Five of 10 matrilineal relatives exhibited variable severity and age at onset of sensorineural hearing loss. The average ages at onset of hearing loss in matrilineal relatives of this family were 29 years. Molecular analysis of their mitochondrial genomes identified the tRNA(Phe) 593T > C variant belonging to Asian haplogroup G2a2a. The m.593T > C variant resided at the position 17 of DHU-loop, where the position is important for the structure and function of tRNA. It was anticipated that the m.593T > C variant altered the structure and function of tRNA(Phe). By using lymphoblastoid cell lines derived from the Chinese family, we showed a 46% decreases in the steady-state level of tRNA(Phe) in mutant cell lines. Western blotting analysis showed 35% reduction in the levels of mitochondrial translation in mutant cell lines carrying the m.593T > C variant. Impaired mitochondrial translation is apparently a primary contributor to the marked reduction in the rate of respiratory capacity. The respiratory deficiency lowed mitochondrial ATP production in the mutant cell lines. These data provide the evidence that mitochondrial dysfunctions caused by the m.593T > C variant lead to late-onset nonsyndromic hearing loss. Thus, our findings may provide the new insights into the understanding of pathophysiology and valuable information for management and treatment of maternally inherited hearing loss.