Coexistence of mitochondrial 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations in two Han Chinese pedigrees with aminoglycoside-induced and non-syndromic hearing loss.
Mutations in mitochondrial DNA are one of the important causes of hearing loss. We report here the clinical, genetic, and molecular characterization of two Han Chinese pedigrees with maternally transmitted aminoglycoside-induced and nonsyndromic bilateral hearing loss. Clinical evaluation revealed the wide range of severity, age-at-onset, and audiometric configuration of hearing impairment in matrilineal relatives in these families. The penetrances of hearing loss in these pedigrees were 20% and 18%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss in these seven pedigrees were 10% and 15%. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the presence of the deafness-associated 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations. Their distinct sets of mtDNA polymorphism belonged to Eastern Asian haplogroup C4a1, while other previously identified six Chinese mitochondrial genomes harboring the C1494T mutation belong to haplogroups D5a2, D, R, and F1, respectively. This suggested that the C1494T or G7444A mutation occurred sporadically and multiplied through evolution of the mitochondrial DNA (mtDNA). The absence of functionally significant mutations in tRNA and rRNAs or secondary LHON mutations in their mtDNA suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations in those Chinese families. However, aminoglycosides and other nuclear modifier genes play a modifying role in the phenotypic manifestation of the C1494T mutation in these Chinese families.
Yuan
Huijun
H
Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
Chen
Jing
J
Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
Liu
Xin
X
Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
Cheng
Jing
J
Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
Wang
Xinjian
X
Division of Human Genetics and Center for Hearing and Deafness Research, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
Yang
Li
L
Division of Human Genetics and Center for Hearing and Deafness Research, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
Yang
Shuzhi
S
Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
Cao
Juyang
J
Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
Kang
Dongyang
D
Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
Dai
Pu
P
Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
Zhai
Suoqiang
S
Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
Han
Dongyi
D
Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China. Electronic address: HDY301@263.com.
Young
Wie-Yen
WY
Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China. Electronic address: YWY@263.com.
Guan
Min-Xin
MX
Division of Human Genetics and Center for Hearing and Deafness Research, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Electronic address: min-xin.guan@cchmc.org.
D000617:Aminoglycosides / Q000494:pharmacology*; D002681:China; D051545:Cyclooxygenase 1 / Q000235:genetics* / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D034381:Hearing Loss / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D012335:RNA, Ribosomal / Q000737:chemistry* / Q000235:genetics*; D012343:RNA, Transfer / Q000378:metabolism; D017422:Sequence Analysis, DNA; D012694:Serine / Q000737:chemistry*
D000617:Aminoglycosides; D004272:DNA, Mitochondrial; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S; D012694:Serine; D012343:RNA, Transfer; D051545:Cyclooxygenase 1