Biology Reference
In-Depth Information
of two half-channels (connexons), each of which is present in either of two
adjacent cells. The half-channels then associate to form a gap junction con-
necting the cells. Each half-channel is composed of six connexin subunits,
and different connexins can oligomerize with each other to form a hetero-
multimeric half-channel (Bruzzone et al. 1996; Goodenough et al. 1996).
The genes encoding proteins that comprise or interact with gap junctions
expressed in the auditory system are therefore good candidate genes for
DFNB and DFNA loci.
Gap junctions are important for intercellular communication and home-
ostasis within the inner ear, as they permit cell-to-cell signaling and passage
of ions such as potassium (Kikuchi et al. 1995). The endolymph has a high
potassium concentration, and potassium flows down a concentration gradi-
ent into the hair cells during transduction of the auditory stimulus within
the cochlea. It is postulated that potassium is recycled to the endolymph
via gap junctions in adjacent support cells and out through fibrocytes of the
stria vascularis (Spicer and Schulte 1998; Spicer and Schulte 1996). Patho-
logical mutations of
GJB2
are predicted to disrupt gap junctions compris-
ing defective connexin 26, and thus interfere with the recycling of potassium
ions in the inner ear. Since connexin 26 gap junctions probably allow inter-
cellular passage of a variety of other small molecules, altered potassium-ion
homeostasis may not completely account for the hearing loss phenotype
associated with
GJB2
mutations.
3.9.4 35delG is a Major Contributor to NSRD in Some Populations
One particular allele of
GJB2
, 35delG, also referred to as 30delG, is a major
contributor to NSRD in some populations (Denoyelle et al. 1997; Scott et
al. 1998b; Zelante et al. 1997). 35delG is a deletion of a single guanine (G)
in a string of six Gs beginning at codon 10, and it is presumed to be a null
allele. This mutation shifts the reading frame, resulting in a predicted pre-
mature chain termination product comprising 12 amino acids, if any at all.
The carrier frequency for 35delG in the United States has been calculated
from small samples and appears to be about 1/100 to 1/200, but may be
higher (Morell et al. 1998; Scott et al. 1998b; Scott et al. 1998a). In French,
Spanish and Italian populations, the carrier frequency for 35delG is 1/25 to
1/43 (Denoyelle et al. 1997; Estivill et al. 1998; Zelante et al. 1997), which
predicts a high proportion of NSRD is due to this one recessive mutation
in these populations. Indeed, 63 to 92% of cases of hereditary nonsyn-
dromic deafness in families originating in Italy, Spain, France, United
Kingdom, Tunisia, Lebanon, Australia and New Zealand are associated with
the 35delG mutation (Denoyelle et al. 1997; Estivill et al. 1998; Kelsell et
al. 1997; Maw et al. 1995; Zelante et al. 1997). Moreover, 35delG accounts
for at least 5% of sporadic cases of NSRD. In a cohort of 68 sporadic NSRD
cases from the United Kingdom and Belgium, three were homozygous for
35delG and three were heterozygous for 35delG. The second
GJB2
muta-
