Deafness, Autosomal Recessive 26, Modifier Of

A number sign (#) is used with this entry because of evidence that modifier of autosomal recessive deafness-26 (DFNB26M) is caused by heterozygous mutation in the METTL13 gene (617987) on chromosome 1q24. Individuals who are homozygous for a deafness-associated mutation in the GAB1 gene (604439) on chromosome 4q31 do not develop deafness if they are also heterozygous for a mutation in the METTL13 gene. One such family has been reported.

Description

DFNB26M is characterized by normal hearing despite the presence of homozygosity for a causative deafness mutation in the GAB1 gene (Yousaf et al., 2018).

Mapping

Riazuddin et al. (2000) mapped a form of autosomal recessive nonsyndromic deafness in a consanguineous Pakistani family (PK2) to chromosome 4q31 (DFNB26; 605428). A maximum lod score of 8.10 at theta = 0.0 was obtained with D4S1610 when only the 8 affected individuals in this family were included in the calculation. There were 7 unaffected family members who were also homozygous for the DFNB26-linked haplotype and thus were nonpenetrant. Riazuddin et al. (2000) mapped a dominant deafness modifier, which they designated DFNM1, that suppressed deafness in the 7 nonpenetrant individuals to a 5.6-cM region on chromosome 1q24, with a lod score of 4.31 at theta = 0.0 for D1S2815. The map location of DFNM1 was within the 22-cM DFNA7 interval (601412), suggesting that the DFNM1 suppressor phenotype and DFNA7 deafness may be phenotypic variants of the same gene.

Molecular Genetics

In a large consanguineous Pakistani family (PK2) with prelingual severe to profound nonsyndromic hearing loss, originally studied by Riazuddin et al. (2000), Yousaf et al. (2018) identified homozygosity for a missense mutation in the GAB1 gene (G116E; 604439.0001) that segregated fully with the DFNB26-linked haplotype present in 8 deaf and 7 nonpenetrant hearing members of the family. In addition, by Sanger sequencing of all annotated genes within the deafness-modifier interval on chromosome 1q24 that had been shown to segregate only with nonpenetrant hearing members of the family, Yousaf et al. (2018) identified heterozygosity for a missense mutation in the METTL13 gene (R544Q; 617987.0001) that segregated fully with nonpenetrance for the deafness phenotype in hearing members of the family who were homozygous for the GAB1 variant. None of the deaf family members carried the METTL13 R544Q variant. Analysis of 37 genes in the MET (164860)-signaling pathway revealed 1 gene, SPRY2 (602466), that was significantly upregulated in deaf family members but not in the nonpenetrant individuals. The authors suggested that differential regulation of SPRY2 might be the mechanism by which the METTL13 variant functions as a modifier to prevent deafness caused by mutation in the GAB1 gene.