The Connexin-deafness homepage
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
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
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
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.