Biology Reference
In-Depth Information
have a 3% carrier frequency for the 30delG mutant allele of
GJB2
and,
therefore, one in 33 people in the general population, including individuals
with hearing loss, will be a 30delG carrier. The detection of a heterozygous
30delG mutation in an individual or a small family with NSRD may simply
be coincidental (Estivill et al. 1998).
Another possibility is that the second mutation may be in another gene,
and the combined action of the two nonallelic mutations gives rise to a
mutant phenotype. Other connexin genes would be good candidates for
harboring the “missing deafness allele,” since it is known that gap junctions
can be heteromultimeric complexes comprising different connexin family
members such as connexin 26, connexin 32, connexin 46 and connexin 50
(Bruzzone et al. 1996).
3.9.7 Hearing Phenotype in Families with
GJB2
and
GJB3
Mutations
There is considerable variation in the hearing phenotype among and within
DFNB1
families. The phenotype may be a congenital moderate to profound
hearing loss, or it might be a progressive loss in some families. Such varia-
tion is indicative of the existence of a modifier gene(s) (Carrasquillo et al.
1997; Denoyelle et al. 1997; Morell et al. 1998; Scott et al. 1998b). The same
modifier genes could also account for the nonpenetrant status of carriers of
the R180X mutant allele of
GJB3
(Scott et al. 1998a; Xia et al. 1998). A
large inbred population with NSRD and significant phenotypic variation
among individuals homozygous for the same allele of
GJB2
(or
GJB3
)
could be useful for mapping and identifying such modifier genes
(Carrasquillo et al. 1997).
Surprisingly, there are a few individuals reported to be homozygous for
the 35delG mutation (presumably devoid of functional connexin 26) who
exhibit mild or progressive hearing loss (Cohn et al. 1999). These observa-
tions indicate that there must be a compensatory pathway in some indi-
viduals for the loss of connexin 26 function in the auditory system.
Manipulation of this compensatory mechanism is one potential approach
to the development of pharmacologic therapy for
DFNB1
individuals with
hearing loss. The considerable variation in hearing loss within and between
families associated with
GJB2
mutant alleles also poses a challenge to
genetic counselors and medical geneticists attempting to inform their
patients of potential risks.
3.9.8 Animal Models for
GJB2
Mapping and identifying the genes modifying the
GJB2
(or
GJB3
) pheno-
type might be more easily achieved in the mouse, where large breeding
crosses can be used to generate many meioses, which facilitate gene local-
ization and identification. However, a homozygous targeted intragenic dele-
tion (null allele) of
Gjb2
in the mouse is reported to result in embryonic
lethality 10 days post-coitum (Gabriel et al. 1998). This is in contrast to the
