title: 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.
abstract: 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.
authors.affiliation: Department of Otolaryngology, The Second Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Bobei
authors.initials: B
authors.lastname: Chen
authors.forename: Dongmei
authors.initials: D
authors.lastname: Sun
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Chuqin
authors.initials: C
authors.lastname: Zhang
authors.forename: Aifen
authors.initials: A
authors.lastname: Yang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jianyue
authors.initials: J
authors.lastname: Zhao
authors.forename: Yingying
authors.initials: Y
authors.lastname: Chen
authors.forename: Minqiang
authors.initials: M
authors.lastname: Guan
authors.forename: Xinjian
authors.initials: X
authors.lastname: Wang
authors.forename: Ronghua
authors.initials: R
authors.lastname: Li
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Tang
authors.forename: Jindan
authors.initials: J
authors.lastname: Wang
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Tao
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lu
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology; D001483:Base Sequence; D002681:China; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D003638:Deafness / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D012335:RNA, Ribosomal / Q000235:genetics*; D012350:RNA, Transfer, Cys / Q000737:chemistry / Q000235:genetics; D012363:RNA, Transfer, Thr / Q000737:chemistry / Q000235:genetics; D012720:Severity of Illness Index; D012359:tRNA Methyltransferases / Q000235:genetics
chemical_list: D000617:Aminoglycosides; D017630:Connexins; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D012335:RNA, Ribosomal; D012350:RNA, Transfer, Cys; D012363:RNA, Transfer, Thr; C075526:RNA, ribosomal, 12S; D000072259:Connexin 26; D012359:tRNA Methyltransferases; C496706:TRMU protein, human