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Mitochondrial ND5 T12338C, tRNA Cys T5802C, and tRNA Thr G15927A variants may have a modifying role in the phenotypic manifestation of deafness‐associated 12S rRNA A1555G mutation in three Han Chinese pedigrees
Author(s) -
Chen Bobei,
Sun Dongmei,
Yang Li,
Zhang Chuqin,
Yang Aifen,
Zhu Yi,
Zhao Jianyue,
Chen Yingying,
Guan Minqiang,
Wang Xinjian,
Li Ronghua,
Tang Xiaowen,
Wang Jindan,
Tao Zhihua,
Lu Jianxin,
Guan MinXin
Publication year - 2008
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.32285
Subject(s) - penetrance , transfer rna , genetics , biology , mitochondrial dna , mutation , expressivity , haplogroup , phenotype , gene , rna , genotype , haplotype
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 aminoglycosides 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. © 2008 Wiley‐Liss, Inc.