title: Maternally transmitted late-onset non-syndromic deafness is associated with the novel heteroplasmic T12201C mutation in the mitochondrial tRNAHis gene.
abstract: 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 tRNA(His). tRNA northern analysis revealed that the T12201C mutation caused an ∼75% reduction in the steady-state level of tRNA(His). 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 tRNA(His) 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.
authors.affiliation: Institute of Genetics, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Xukun
authors.initials: X
authors.lastname: Yan
authors.forename: Xinjian
authors.initials: X
authors.lastname: Wang
authors.forename: Zhengmin
authors.initials: Z
authors.lastname: Wang
authors.forename: Shan
authors.initials: S
authors.lastname: Sun
authors.forename: Guoling
authors.initials: G
authors.lastname: Chen
authors.forename: Yingzi
authors.initials: Y
authors.lastname: He
authors.forename: Jun Qin
authors.initials: JQ
authors.lastname: Mo
authors.forename: Ronghua
authors.initials: R
authors.lastname: Li
authors.forename: Pingping
authors.initials: P
authors.lastname: Jiang
authors.forename: Qin
authors.initials: Q
authors.lastname: Lin
authors.forename: Mingzhi
authors.initials: M
authors.lastname: Sun
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lu
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Yan
authors.forename: Huawei
authors.initials: H
authors.lastname: Li
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015152:Blotting, Northern; D002478:Cells, Cultured; D002648:Child; D002681:China; D004272:DNA, Mitochondrial / Q000235:genetics*; D005190:Family; D005260:Female; D050259:Genes, Mitochondrial; D034381:Hearing Loss / Q000235:genetics*; D006320:Hearing Tests; D006801:Humans; D008297:Male; D008875:Middle Aged; D009035:Mothers; D009154:Mutation; D010101:Oxygen Consumption / Q000235:genetics; D010375:Pedigree; D012354:RNA, Transfer, His / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial; D012354:RNA, Transfer, His