Deafness, Autosomal Recessive 26

A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-26 (DFNB26) is caused by homozygous mutation in the GAB1 gene (604439) on chromosome 4q31. Homozygous individuals who also carry a heterozygous mutation in the METTL13 gene (617987) on chromosome 1q24 do not develop deafness (see DFNB26M; 605429). One such family has been reported.

Description

DFNB26 is characterized by prelingual severe to profound nonsyndromic hearing loss (Yousaf et al., 2018).

Mapping

In a consanguineous Pakistani family (PK2), Riazuddin et al. (2000) mapped an autosomal recessive nonsyndromic deafness locus, DFNB26, to a 1.5-cM interval of chromosome 4q31. 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) also mapped a dominant deafness modifier, designated DFNM1 (605429), 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.

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) performed Sanger sequencing of all annotated genes within the DFNB26 linkage interval and 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, 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 the 7 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)/HGF (142409)-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 GAB1-associated deafness.

Reviews

Nadeau (2001) reviewed modifier genes in mice and humans, dividing the types of modification as follows: reduced penetrance, dominance modification, expressivity, and pleiotropy. The DFNB26 gene results in reduced penetrance.