Human mitochondrial transcription factor B1 as a modifier gene for hearing loss associated with the mitochondrial A1555G mutation

Yelena Bykhovskaya, Emebet Mengesha, Dai Wang, Huiying Yang, Xavier Estivill, Mordechai Shohat, Nathan Fischel-Ghodsian

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Phenotypic expression of the deafness-associated homoplasmic A1555G mutation in the mitochondrial 12S rRNA gene varies from profound congenital hearing loss to normal hearing. It has been shown that this variability in clinical expression in most patients is due to the complex inheritance of multiple nuclear-encoded modifier genes. Human mitochondrial transcription factor B1 (TFB1M) has been proposed as a candidate for being such a modifier, since it methylates adenine residues in the adjacent loop of the A1555G mutation in the 12S rRNA gene. Polymorphic markers within and adjacent to the TFB1M gene were genotyped in 214 individuals from 41 multiplex families with the A1555G mutation of Spanish, Italian, and Arab-Israeli origin. Multipoint non-parametric linkage analysis of all families combined revealed an NPL score of 1.7 (P=0.05), and a Lod score of 1.4 (P=0.04). Linkage disequilibrium by the Transmission Disequilibrium Test at D6S1577, a microsatellite adjacent to TFB1M, showed preferential non-transmission of an allele to affected individuals with χ2=8.76; P=0.003. Sequence analysis of the coding region of the gene and testing of all intragenic SNPs did not reveal a putative causative mutation. These data provide suggestive evidence that TFB1M is a nuclear-encoded modifier gene for phenotypic expression of the A1555G mutation, and that the effect may occur through a regulatory or splicing mutation.

Original languageEnglish
Pages (from-to)27-32
Number of pages6
JournalMolecular Genetics and Metabolism
Issue number1
Publication statusPublished - 1 May 2004



  • Candidate gene
  • Complex disease
  • Deafness
  • Linkage disequilibrium
  • Mitochondrial DNA
  • Mitochondrial transcription factor
  • Modifier gene
  • RRNA methylation

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

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