Biology Reference
In-Depth Information
members and, therefore, may be important for connexin 26 function.
However, demonstration of co-segregation of R75W with deafness and/or
PPK in a large family is required in order to establish a causal connection.
M34T is another controversial variant allele of
GJB2
that has been
reported to co-segregate with dominant hearing loss in one family with
three affected individuals. M34T did not co-segregate with a PPK pheno-
type, which was also segregating in this same family (Kelsell et al. 1997).
Scott and coworkers (1998a) subsequently reported a family with three
normal-hearing members who were each heterozygous for M34T, leading
them to suggest that it is not a dominant mutant allele. We have also
observed the M34T allele in a nonsyndromic recessive deafness kindred
where it did not co-segregate with the hearing-loss phenotype, indicating
that it is likely to be a polymorphism (Griffith et al. 2000a).
The functional significance of the M34T mutation has been addressed by
electrophysiologic approaches. The channel-forming ability of connexin 26
subunits containing the M34T mutation has been examined in vivo by cou-
pling
Xenopus laevis
oocytes or HeLa cells expressing the connexin 26 sub-
units and measuring intercellular conductance (Martin et al. 1999; White et
al. 1998). The wild-type allele of
GJB2
produced robust conductances, indi-
cating high levels of channel activity (Martin et al. 1999; White et al. 1998).
On the other hand, the M34T product and a well characterized recessive
allele of
GJB2
, W77R (Kelsell et al. 1997; Scott et al. 1998b), both failed
to induce significant intercellular conductance. Moreover, intercellular
conductance was significantly reduced in coupled
Xenopus
oocytes co-
expressing the M34T allele and the wild-type
GJB2
allele, indicating a
dominant negative effect of M34T (White et al. 1998). The validity of extra-
polating these results of the coupled
Xenopus
oocyte or HeLa cell assay to
the in vivo effects of
GJB2
variant alleles on auditory function has not been
established. Co-segregation of these alleles with dominant deafness in large
families is required in order to conclude that they are indeed dominant
mutant alleles.
There are reports of hearing-impaired individuals in which only one of
two mutant
GJB2
alleles in a presumed compound heterozygote could be
found. In some families with nonsyndromic recessive deafness, many of
which are too small for linkage analysis, only one recessive mutant allele of
GJB2
was identified (Denoyelle et al. 1997; Scott et al. 1998b). Cohn and
coworkers (1999) found only one mutant allele of
GJB2
in 6 of 68 families
with NSRD. There are several reasons the partnering
GJB2
mutant
allele might not have been found: The second allele may be in a region of
GJB2
that was not screened for mutations, including the cis-acting regula-
tory elements of the promoter, the 5ยข untranslated region (UTR), or the
intron.
A parsimonious explanation for not finding the second mutant recessive
allele of
GJB2
in some individuals with NSRD is that it is not present and
GJB2
mutations are not the cause of the hearing loss. Some populations
