title: A six-generation Chinese family in haplogroup B4C1C exhibits high penetrance of 1555A > G-induced hearing Loss.
abstract: BACKGROUND
  The 1555A > G mutation is the most common cause of aminoglycoside-induced and non-syndromic deafness. However, the variable clinical phenotype and incomplete penetrance of A1555G-induced hearing loss complicate our understanding of this mutation. Environmental factors, nuclear genes, mitochondrial haplotypes/variants and a possible threshold effect have been reported to may be involved in its manifestation.
  
  
  METHODS
  Here, we performed a clinical, molecular, genetic and phylogenic analysis in a six-generation Chinese family.
  
  
  RESULTS
  A clinical evaluation revealed that affected individuals without aminoglycoside exposure developed hearing loss extending gradually from 12000 Hz to 8000 Hz and then to 4000 Hz. Using pyrosequencing, we detected an identical homoplasmic 1555A > G mutation in all individuals except one. We did not find any correlation between the mutation load and the severity of hearing loss. T123N coexisted with the 1555A > G mutation in six affected subjects in our pedigree. Analysis of the complete mtDNA genome of this family revealed that this family belonged to haplotype B4C1C and exhibited high penetrance. Upon the inclusion of subjects that had been exposed to aminoglycosides, the penetrance of the hearing loss was 63.6%.; without exposure to aminoglycosides, it was 51.5%. This pedigree and another reported Chinese pedigree share the same haplotype (B4C1C) and lack functionally significant mitochondrial tRNA variants, but nevertheless they exhibit a different penetrance of hearing loss.
  
  
  CONCLUSIONS
  Our results imply that the factors responsible for the higher penetrance and variable expression of the deafness associated with the 1555A > G mutation in this pedigree may not be mtDNA haplotype/variants, but rather nuclear genes and/or aminoglycosides.
authors.affiliation: Department of Otolaryngology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai 200031, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.forename: Zhengmin
authors.initials: Z
authors.lastname: Wang
authors.forename: Wenjia
authors.initials: W
authors.lastname: Dai
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Li
authors.forename: Guoling
authors.initials: G
authors.lastname: Chen
authors.forename: Ning
authors.initials: N
authors.lastname: Cong
authors.forename: Minxin
authors.initials: M
authors.lastname: Guan
authors.forename: Huawei
authors.initials: H
authors.lastname: Li
mesh_terms: D000225:Adenine; D000617:Aminoglycosides / Q000494:pharmacology; D044466:Asian People / Q000235:genetics; D002681:China; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics*; D003638:Deafness / Q000139:chemically induced / Q000235:genetics*; D005260:Female; D006147:Guanine; D006239:Haplotypes / Q000235:genetics; D034381:Hearing Loss / Q000139:chemically induced / Q000235:genetics*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012359:tRNA Methyltransferases / Q000235:genetics*
chemical_list: D000617:Aminoglycosides; D017630:Connexins; D017931:DNA Primers; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D000072259:Connexin 26; D006147:Guanine; D012359:tRNA Methyltransferases; C496706:TRMU protein, human; D000225:Adenine
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