Connexin 26 and deafness

DFNB1, a frequent locus for deafness

The first locus defined for recessive deafness (DFNB1) on chromosome 13q11, was identified by homozygosity mapping in consanguineous families from Tunisia (Guilford et al. 1994). A posterior study in 19 families from Celtic origin suggested an important contribution of this locus in the Caucasoid population (Maw et al. 1995), whereas a study in consanguineous kindreds from Pakistan yielded only one family linked to DFNB1 (Brown et al. 1996). Another study in 48 families from Italy and Spain stressed the importance of this locus in hearing impairment in the Mediterranean population and further localized DFNB1 to the region between markers D13S175 and D13S115, separated by approximately 14 cM (Gasparini et al. 1997).

DFNA3, a dominant deafness locus

A large French dominant family affected by pre-lingual deafness showed linkage on chromosome 13q12 (DFNA3)(Chaib et al. 1994), the same region to which DFNB1 had been mapped.

GJB2 causes dominant and recessive deafness

Kelsell et al. (1997) searched for mutations in the GJB2 (Connexin26) gene in a family in which palmoplantar keratoderma (PPK) co-occurred with dominant sensorineural deafness. The study was based on the assumption that GJB2 was a good candidate for PPK, due to the potential overexpression of Cx26 in the epidermis. Although these investigators did not find mutations segregating with PPK, they detected a T to C substitution at codon 34 that leads to the change of methionine to threonine (M34T) in the patients with deafness of this family. Since GJB2 maps in the chromosomal region where DFNA3 and DFNB1 are localized, the authors analyzed a large Pakistani family linked to DFNB1 (Brown et al. 1996) and identified homozygosity for a nonsense mutation (W77X) in the patients with deafness of this family. They identified another nonsense mutation (W24X) in two other Pakistani families.

In an independent approach of positional cloning and candidate gene analysis of the DFNB1 locus, Zelante et al. (1997) observed several recombinations which narrowed the candidate region for DFNB1 to approximately 5 cM between D13S141 and D13S232. Since genomic mapping data had placed the GJB2 gene (; Mignon et al. 1996) within the interval defined by linkage studies, and previous work showed that cochlea cells are interconnected via gap junctions, which are formed by connexons containing Cx26 (Kikuchi et al. 1995), the GJB2 gene was analyzed for mutations in samples from affected subjects. A single mutation consisting in the deletion of one G within a stretch of six Gs at positions 30 to 35 of GJB2, named 35delG, was found in 63% of the chromosomes with linkage to chromosome 13. Another patient had a deletion of one T at position 167 (167delT), also causing premature chain termination. Thus, the data of Zelante et al. (1997) confirmed that GJB2 is the DFNB1 locus and defined a major mutation (35delG) present in patients of Caucasoid origin.

Common mutations in GJB2

Among the mutations described in GJB2, 35delG (Zelante et al. 1997) (also named 30delG) has been found to be common in most of the populations studied (Carrasquillo et al. 1997; Denoyelle et al. 1997; Zelante et al. 1997; Estivill et al. 1998; Kelley et al. 1998; Lench et al. 1998a; Lench et al. 1998b; Scott et al. 1998b), especially in the Mediterranean region.

Mutation 167delT (Zelante et al. 1997) has been found to be common in patients of Jewish origin (Kelley et al. 1998; Morell et al. 1998). Mutation 235delC has been found to be common among the Asian population (Japanese) (Fuse et al. 1999).
Several other mutations have been described in GJB2, most of them found in few individuals.

Dominant GJB2 mutations

Five GJB2 mutations have been described to cause dominant deafness (M34T, Kelsell et al. 1997; W44C, Denoyelle et al. 1998; W44S, Gasparini et al. Personal communication; R75W, Richard et al. 1998a; and D66H, Maestrini et al 1999).
M34T has been found in heterozygosity in a family with few affected subjects (Kelsell et al. 1997), but also in normal subjects (Kelley et al. 1998;Scott et al. 1998a, 1998b) and in a recessive family (Kelley et al. 1998). It is believed that M34T is a dominant mutation with reduced penetrance. White et al. (1998) performed functional studies on some mutations by expression in Xenopus Laevis oocytes, and showed that M34T had a dominant negative effect, whereas the recesive mutation W77R did not.

W44C was identified as the cause of deafness in several families with non-syndromic autosomic dominant deafness ( Denoyelle et al. (1998)).

Richard et al. (1998a) identified mutation R75W in two affected members of a family with deafness and diffuse keratoderma. The investigators also demonstrated that R75W has a dominant negative effect in functional experiments in vitro.

A missense mutation (D66H) in connexin 26 has been identified in three families presenting sensorineural deafness and mutilating keratoderma (Maestrini et al. 1999). The mutation seems to be totally penetrant, as all patients in the three pedigrees presenting D66H were affected.

Another GJB2 mutation, G59A (Heathcote et al. 2000), has been recently identified in a family with dominant deafness and hyperkeratosis. All affected members of the family inherited the G59A mutation in GJB2. Another mutation in this gene, F83L was identified in only two subjects, one affected and one not.