title: Cosegregation of the G7444A mutation in the mitochondrial COI/tRNA(Ser(UCN)) genes with the 12S rRNA A1555G mutation in a Chinese family with aminoglycoside-induced and nonsyndromic hearing loss.
abstract: We report here on the characterization of a three-generation Chinese family with aminoglycoside-induced and nonsyndromic hearing impairment. Ten of 17 matrilineal relatives exhibited bilateral and sensorineural hearing impairment. Of these, nine matrilineal relatives, who had a history of exposure to aminoglycosides, exhibited variable severity and audiometric configuration of hearing loss. The dose and age at the time of drug administration seemed to be correlated with the severity of the hearing loss experienced by affected individuals. Sequence analysis of the complete mitochondrial genome in the pedigree showed the presence of homoplasmic A1555G mutation and 37 variants belonging to haplogroup D4a. Of those variants, the G7444A mutation is of special interest as the mutation at this position results in a read-through of the stop condon AGA of the COI message, thereby adding three amino acids (Lys-Gln-Lys) to the C-terminal of the polypeptide. Alternatively, the G7444A mutation is adjacent to the site of 3' end endonucleolytic processing of L-strand RNA precursor, spanning tRNA(Ser(UCN)) and ND6 mRNA. Thus, the G7444A mutation, similar to the deafness-associated A7445G mutation, may lead to a defect in the processing of the L-strand RNA precursor, thus influencing the phenotypic expression of the A1555G mutation. These data also imply that nuclear background plays a role in the aminoglycoside ototoxicity associated with the A1555G mutation in this Chinese pedigree.
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Yuan
authors.forename: Yaping
authors.initials: Y
authors.lastname: Qian
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Xu
authors.forename: Juyang
authors.initials: J
authors.lastname: Cao
authors.forename: Linna
authors.initials: L
authors.lastname: Bai
authors.forename: Weidong
authors.initials: W
authors.lastname: Shen
authors.forename: Fei
authors.initials: F
authors.lastname: Ji
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Dongyang
authors.initials: D
authors.lastname: Kang
authors.forename: Jun Qin
authors.initials: JQ
authors.lastname: Mo
authors.forename: John H
authors.initials: JH
authors.lastname: Greinwald
authors.forename: Dongyi
authors.initials: D
authors.lastname: Han
authors.forename: Suoqiang
authors.initials: S
authors.lastname: Zhai
authors.forename: Wie-Yen
authors.initials: WY
authors.lastname: Young
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000617:Aminoglycosides; D001483:Base Sequence; D002648:Child; D002681:China; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics; D005192:Family Health; D005260:Female; D034381:Hearing Loss / Q000139:chemically induced / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D012335:RNA, Ribosomal / Q000235:genetics; D012362:RNA, Transfer, Ser / Q000235:genetics
chemical_list: D000617:Aminoglycosides; D004272:DNA, Mitochondrial; D012335:RNA, Ribosomal; D012362:RNA, Transfer, Ser; C075526:RNA, ribosomal, 12S; D003576:Electron Transport Complex IV