Phenotypic variability of non-syndromic hearing loss in patients heterozygous for both c.35delG of GJB2 and the 342-kb deletion involving GJB6

Abstract

Mutations in GJB2, encoding the gap junction protein connexin 26, are the most common cause of inherited non-syndromic hearing loss (NSHL), with a broad spectrum of mutations leading to recessive as well as dominant forms. It has been shown that patients who are compound heterozygous for a 342-kb deletion (Δ(GJB6-D13S1830)) involving a large portion of the 5′-part of GJB6, encoding connexin 30, and a GJB2 mutation develop NSHL due to a trait with a digenic pattern of inheritance. We have used a mutation-specific polymerase chain reaction assay to screen NSHL patients for the presence of Δ(GJB6-D13S1830) and identified two families segregating both c.35delG in GJB2 and Δ(GJB6-D13S1830). Remarkably, the severity of hearing loss due to heterozygosity for c.35delG in GJB2 in conjunction with Δ(GJB6-D13S1830) is considerably different in members of the two families, ranging from congenital deafness in one to moderate/severe hearing loss with congenital onset in the other case.

Introduction

Moderate to severe hearing loss affects about 1 in 1000 newborns, and a genetic basis is assumed in at least 50% of the cases. Defects in probably more than 100 different genes can cause autosomal recessive (DFNB), autosomal dominant (DFNA), X-linked (DFN), or mitochondrial hearing loss, both non-syndromic (NSHL) and syndromic, demonstrating significant genetic heterogeneity of this sensory disorder. While defects in most of the known deafness genes are extremely rare causes of NSHL, those in a small number of genes are common. Mutations in the gene GJB2 (encoding the gap junction protein connexin 26) underlie, depending on the population studied, up to 63% of autosomal recessive NSHL cases (Kelsell et al., 1997; http://dnalab-www.uia.ac.be/dnalab/hhh/hhh). GJB2 probably plays an important role in the recycling pathway of potassium that enters the hair cell during the process of auditory signal transduction (Richard et al., 1998).

The observation that patients from some families with a disease locus showing linkage to the DFNB1 locus on chromosome 13, corresponding to the GJB2 gene, have only one mutant GJB2 allele has led to further investigation. It was shown that some of these cases represented a digenic form of inheritance, resulting from simultaneous heterozygosity for two non-allelic mutations, a GJB2 mutation and a large, 342-kb deletion removing a large part of the 5′-portion of GJB6 (del Castillo et al., 2002, Lerer et al., 2001, Pallares-Ruiz et al., 2002), the gene encoding another gap junction protein, connexin 30, and located approximately 35 kb telomeric of GJB2. As the deletion also comprises the microsatellite marker D13S1830, it has been termed Δ(GJB6-D13S1830). Connexin 30 co-localizes with GJB2 in the different inner ear tissues (Lautermann et al., 1998, Lautermann et al., 1999) and participates in the formation of heterotypic GJB2/GJB6 gap junction channels. Mutations in GJB6 account for both autosomal recessive and autosomal dominant NSHL (del Castillo et al., 2002, Grifa et al., 1999). Individuals with GJB2 mutations on both alleles usually present with prelingual, moderate to profound NSHL (Janecke et al., 2002). For subjects carrying both c.35delG (GJB2) and Δ(GJB6-D13S1830) described to date, hearing loss was prelingual and profound (del Castillo et al., 2002, Lerer et al., 2001, Pallares-Ruiz et al., 2002).