Mitochondrial ND5 T12338C, tRNACys T5802C, and tRNAThr G15927A variants may have a modifying role in the phenotypic manifestation of deafness-associated 12S rRNA A1555G mutation in three Han Chinese pedigrees
Mitochondrial ND5 T12338C, tRNACys T5802C, and tRNAThr G15927A variants may have a modifying role in the phenotypic manifestation of deafness-associated 12S rRNA A1555G mutation in three Han Chinese pedigrees
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DOI：
10.1002/ajmg.a.32285
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发表时间：
2008-05-15
影响因子：
2
通讯作者：
Guan, Min-Xin
中科院分区：
文献类型：
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作者：
Chen, Bobei;Sun, Dongmei;Guan, Min-Xin
我们报告了三个汉族人氨基糖苷类诱导性和非综合征性听力损失的临床、遗传和分子特征。临床评估显示，这些受试者的听力损害有不同的表型，包括严重程度、发病年龄、听力结构。如果计入氨基糖苷类耳聋，WZD8、WZD9和WZD10家系的听力损失外显率分别为46%、46%和50%。剔除氨基糖苷类药物的影响后，这些家系的听力损失外显率分别为23%、31%和37.5%。对线粒体全基因组的突变分析表明，A1555G为同质突变，单倍群D4b2b、B5b1和F2分别存在不同的线粒体DNA变异。其中，tRNA(Cys)T5802C、tRNA(Thr)A15924C和ND5 T12338C变异是特别感兴趣的，因为这些变异发生在进化高度保守的tRNA核苷酸或多肽氨基酸的位置。在156名无血缘关系的中国对照中，这些同质线粒体DNA变异体缺失。T5802C和G15927A突变破坏了tRNA(Cys)或tRNA(Thr)反密码子茎上高度保守的A-U或C-G碱基配对，而ND5 T12338C突变导致翻译启动的蛋氨酸被苏氨酸取代，并位于tRNA 3‘端的两个核苷酸(Leu(Cun))上。因此，由A1555G突变引起的线粒体功能障碍将因这些mtDNA变异而恶化。因此，这些线粒体DNA突变可能在增加耳聋相关的12S rRNA A1555G突变在中国人中的外显率和表达能力方面具有潜在的调节作用。(C)2008年Wiley-Liss，Inc.
We report here on the clinical, genetic, and molecular characterization of three Han Chinese pedigrees with aminoglycoside-induced and nonsyndromic hearing loss. Clinical evaluation revealed the variable phenotype of hearing impairment including severity, age-at-onset, audiometric configuration in these subjects. The penetrance of hearing loss in WZD8, WZD9, and WZD10 pedigrees were 46%, 46%, and 50%, respectively, when aminoglycoside-induced deafness was included. When the effect of amino-glycosides was excluded, the penetrance of hearing loss in these pedigrees were 23%, 31%, and 37.5%, respectively. Mutational analysis of the complete mitochondrial genomes showed the homoplasmic A1555G mutation and distinct sets of mitochondrial DNA variants belonging to haplogroups D4b2b, B5b1, and F2, respectively. Of these, the tRNA(Cys) T5802C, tRNA(Thr) A15924C, and ND5 T12338C variants are of special interest as these variants occur at positions which are highly evolutionarily conserved nucleotides of tRNAs or amino acid of polypeptide. These homoplasmic mtDNA variants were absent among 156 unrelated Chinese controls. The T5802C and G15927A variants disrupted a highly conserved A-U or C-G base-pairing at the anticodon-stem of tRNA(Cys) or tRNA(Thr), while the ND5 T12338C mutation resulted in the replacement of the translation-initiating methionine with a threonine, and also located in two nucleotides adjacent to the 3' end of the tRNA(Leu(CUN)). Thus, mitochondrial dysfunctions, caused by the A1555G Mutation, would be worsened by these mtDNA variants. Therefore, these mtDNA mutations may have a potential modifier role in increasing the penetrance and expressivity of the deafness-associated 12S rRNA A1555G mutation in those Chinese pedigrees. (C) 2008 Wiley-Liss, Inc.