84d9938a-bcfd-40db-8102-380c06412388
title
Human mitochondrial transcription factor B1  as a modifier gene for hearing loss associated with the mitochondrial  A1555G  mutation.
14aac224-f23b-447d-abd8-daebc379d1d1
abstract
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 chi2 = 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.