Biology Reference
In-Depth Information
tion, if it exists in these latter individuals, was not identified (Lench et al.
1998).
3.9.5 167delT Mutation of
GJB2
in Ashkenazi Jews
The limited epidemiological data on the incidence of profound, congenital,
hereditary hearing loss among Ashkenazi Jews indicate that the prevalence
of NSRD among Ashkenazi Jews is roughly 1 in 2,000. The
GJB2
35delG
carrier frequency is 0.73%, also approximately the same as in the general
United States population (Brownstein et al. 1991; Feinmesser et al. 1990).
However, a screen of 550 representative, unrelated Ashkenazi Jews demon-
strated a carrier frequency of 4.03% for the 167delT mutant allele of
GJB2
,
which is rare in the general population (Morell et al. 1998). A conserved
haplotype of genetic markers flanking the 167delT mutation was reported.
A carrier frequency of 4.76% for just two
GJB2
mutant alleles (4.03% for
167delT and 0.73% for 30delG) would predict a prevalence of one deaf
person in 1,765 individuals and could account for much of the recessive
hearing loss among the Ashkenazim (Morell et al. 1998). The high carrier
frequency of 167delT in the Ashkenazim may have been caused by a pre-
vious reduction in population size followed by an expansion, an event
referred to as a population bottleneck. A study of idiopathic torsion dys-
tonia predicted a population bottleneck among Ashkenazi Jews about 12
to 13 generations ago (Risch et al. 1995).
3.9.6 Dominant Mutant Alleles of
GJB2
:
DFNB1
and
DFNA3
are the Same Locus
Two alleles of
GJB2
have been reported to be associated with dominant
hearing loss. A dominant allele causing nonsyndromic progressive
high-frequency hearing loss was mapped to chromosome 13q12 in two fam-
ilies with a total of 30 affected individuals. The locus was designated
DFNA3
(Chaib et al. 1994). In both of these families, a G-to-C transver-
sion was identified at codon 44 of
GJB2
, which is predicted to substitute
cysteine for tryptophan (W44C). This dominant allele of
GJB2
was not
observed in 380 chromosomes from unrelated, representative individuals,
and thus appears not to be a polymorphism (Denoyelle et al. 1998). A
second dominant allele of
GJB2
, D66H, has been shown to co-segregate
with a syndromic form of deafness known as Vohwinkel's syndrome in three
unrelated families, including one large family (Maestrini et al. 1999).
Vohwinkel's syndrome is characterized by mutilating keratoderma and sen-
sorineural hearing loss.
Other reports of dominant deafness alleles of
GJB2
have not been so
convincing. For example, there is a report of a father and daughter co-
segregating profound deafness and palmoplantar keratoderma (PPK) with
a heterozygous missense allele of
GJB2
, R75W (Richard et al. 1998).
The arginine at residue 75 is conserved among all connexin gene family
