Biology Reference
In-Depth Information
Several questions remain about
POU4F3
and hearing loss in humans.
Why is the 8 bp deletion of human
POU4F3
a dominant mutation, while a
Pou4f3
null mutation in mice is recessive? It is possible that the human
mutation is a neomorph resulting in a
POU4F3
protein with a new or
altered function. What are the roles of the target genes of
POU4F3
in the
development and function of the auditory system? The target genes of
POU4F3
are good candidates for DFNA and DFNB loci that have not yet
been identified.
3.9 DFNB1
3.9.1 Linkage Analysis and Identification of
DFNB1
Nonsyndromic recessive deafness (NSRD) segregating in two consan-
guineous families from Tunisia was mapped by linkage analysis to 13q12
(Guilford et al. 1994a). Many other consanguineous and nonconsan-
guineous families from different ethnic populations were subsequently
shown to also map to
DFNB1
(Brown et al. 1996; Gasparini et al. 1997;
Maw et al. 1995; Scott et al. 1995).
DFNB1
therefore appeared to be a major
contributor to hereditary deafness in some populations.
3.9.2 GJB2 Encodes Connexin 26
By virtue of its expression pattern in the inner ear and its location at 13q12,
GJB2
(Gap Junction Protein Beta 2) was examined for mutations co-
segregating with NSRD in
DFNB1
families. In two
DFNB1
-linked Pak-
istani families, two different nonsense mutations of
GJB2
were identified
(Kelsell et al. 1997). Subsequently,
GJB2
mutations causing NSRD were
identified in a large inbred Israeli-Arab family, a Caucasian family, an Israeli
family and a Dominican/Puerto Rican family (Carrasquillo et al. 1997; Scott
et al. 1998b).
GJB2
(or connexin 26,
Cx26
) has a simple genomic structure comprising
two exons. Exon 1 encodes the 5ยข untranslated region, while exon 2 encodes
the entire 208 amino acid open-reading frame. Because of the small size, a
screen for mutations in
GJB2
can be quickly accomplished by SSCP analy-
sis, or more definitively by sequencing the two
GJB2
exons. Many different
mutant
GJB2
alleles (http://www.iro.es/cx26deaf.html), all located in exon
2 and predicted to inactivate
GJB2
, have been identified in NSRD families
from many parts of the world (Carrasquillo et al. 1997; Morell et al. 1998;
Scott et al. 1998b).
3.9.3 Connexin Gene Family and Gap Junctions
There are at least thirteen members of the connexin gene family in rodents.
Connexins are proteins that comprise gap junctions, which electrophysically
couple neighboring cells (Bruzzone et al. 1996). A gap junction is composed
