Maternally transmitted late-onset non-syndromic deafness is associated with the novel heteroplasmic T12201C mutation in the mitochondrial tRNAHis gene
Maternally transmitted late-onset non-syndromic deafness is associated with the novel heteroplasmic T12201C mutation in the mitochondrial tRNAHis gene
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DOI：
10.1136/jmedgenet-2011-100219
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发表时间：
2011-09
影响因子：
4
通讯作者：
Xukun Yan;Xinjian Wang;Zhengmin Wang;Shan Sun;Guoling Chen;Yingzi He;J. Mo;Ronghua Li;Pingping Jiang;Qin Lin;Ming-dong Sun;Wen Li;Yan Bai;Jianning Zhang;Yi Zhu;Jianxin Lu;Qingfeng Yan;Huawei Li;M. Guan
中科院分区：
文献类型：
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作者：
Xukun Yan;Xinjian Wang;Zhengmin Wang;Shan Sun;Guoling Chen;Yingzi He;J. Mo;Ronghua Li;Pingping Jiang;Qin Lin;Ming-dong Sun;Wen Li;Yan Bai;Jianning Zhang;Yi Zhu;Jianxin Lu;Qingfeng Yan;Huawei Li;M. Guan
作者在此报告了一个五代汉族母系遗传性非综合征性耳聋家系的临床、遗传、分子和生化特征。35例母系亲属中有17例表现出不同的严重程度和发病年龄。该家族的母系亲属听力损失的平均发病年龄为29岁，而携带其他线粒体DNA突变的家族中的母系亲属在先天性条件下或发病年龄较早时发生听力损失。他们的线粒体基因组的分子分析确定了新的异质性T12201 C突变的转移RNA（tRNA）的His基因。该家系母系亲属T12201 C突变水平与非综合征性听力损失的严重程度和发病年龄相关。相比之下，其他异质性线粒体DNA突变通常会导致综合征性听力损失。T12201 C突变破坏了tRNAHis受体茎上高度保守的碱基配对（5A-68 U）。tRNA北方分析显示，T12201 C突变导致稳定状态的tRNAHis水平降低约75%。体内蛋白质标记分析显示，携带T12201 C突变的细胞的线粒体翻译速率降低了约47%。受损的线粒体翻译显然是总体呼吸能力、苹果酸/谷氨酸促进的呼吸、琥珀酸/甘油-3-磷酸促进的呼吸或N，N，N，N，N-四甲基-对苯二胺/抗坏血酸促进的呼吸速率显著降低的主要原因。这些数据提供了第一个直接的证据，线粒体功能障碍引起的异质性tRNAHis突变导致迟发性非综合征性耳聋。因此，作者的发现为理解病理生理学提供了新的见解，并为管理和治疗母系遗传性听力损失提供了有价值的信息。
The authors report here the clinical, genetic, molecular and biochemical characterisation of a large five-generation Han Chinese pedigree with maternally transmitted non-syndromic hearing loss. 17 of 35 matrilineal relatives exhibited variable severity and age at onset of sensorineural hearing loss. The average age at onset of hearing loss in matrilineal relatives of this family is 29 years, while matrilineal relatives among families carrying other mitochondrial DNA mutations developed hearing loss with congenital conditions or early age at onset. Molecular analysis of their mitochondrial genome identified the novel heteroplasmic T12201C mutation in the transfer RNA (tRNA)His gene. The levels of T12201C mutation in matrilineal relatives of this family correlated with the severity and age at onset of non-syndromic hearing loss. By contrast, other heteroplasmic mitochondrial DNA mutations often cause syndromic hearing loss. The T12201C mutation destabilises a highly conservative base-pairing (5A-68U) on the acceptor stem of tRNAHis. tRNA northern analysis revealed that the T12201C mutation caused an ∼75% reduction in the steady-state level of tRNAHis. An in vivo protein labeling analysis showed an ∼47% reduction in the rate of mitochondrial translation in cells carrying the T12201C mutation. Impaired mitochondrial translation is apparently a primary contributor to the marked reduction in the rate of overall respiratory capacity, malate/glutamate-promoted respiration, succinate/glycerol-3-phosphate-promoted respiration or N,N,Ń,Ń-tetramethyl-p-phenylenediamine/ascorbate-promoted respiration. These data provide the first direct evidence that mitochondrial dysfunctions caused by the heteroplasmic tRNAHis mutation lead to late-onset non-syndromic deafness. Thus, the authors' findings provide new insights into the understanding of pathophysiology and valuable information on the management and treatment of maternally inherited hearing loss.