Biology Reference
In-Depth Information
these families from the Netherlands (de Kok et al. 1999). In other Dutch
families and in a Belgian family, the Pro51Ser allele of
COCH
also is
responsible for dominantly inherited, progressive vestiulocochlear prob-
lems linked to 14q12-13 (Fransen et al. 1999). In some members of these
families, the symptoms of episodes of vertigo, fluctuating hearing loss and/or
tinnitus is similar to descriptions of individuals with Ménière's disease.
3.8 DFNA15
A five-generation Israeli Jewish family segregating autosomal dominant,
progressive deafness had twelve affected members. The onset of hearing
loss occurred by 18 to 30 years of age and progressed to moderate to severe
levels by 40 years of age, with full penetrance (Frydman et al. 2000; Vahava
et al. 1998). Markers linked to the known DFNA and DFNB loci were
tested for linkage to the hearing loss phenotype in this family. Markers in
the
DFNA1
interval at 5q31-q33 showed weak positive linkage at distant
recombination fractions from
DFNA1
(Lynch et al. 1997), suggesting that
mutations for deafness in the Costa Rican family and the Israeli family were
not allelic, but that the two genes are linked. Haplotype analysis defined
a 25 cM interval for this new locus on 5q, which was designated
DFNA15
.
This 25 cM critical region was too large to support the use of a positional
or functional cloning strategy.
A mouse model suggested a good candidate gene in the region,
POU4F3
.
The mouse orthologue,
Pou4f3
, is a member of a family of genes encoding
transcription factors, and is necessary for differentiation of sensorineural
cells of the auditory system, where it appears to be exclusively expressed
(Erkman et al. 1996; McEvilly et al. 1996). A targeted null mutation of
Pou4f3
causes deafness in homozygous mice (Erkman et al. 1996). Mouse
Pou4f3
is located on chromosome 18 in a region of conserved synteny with
human 5q. Since the human orthologue,
POU4F3
, mapped to human 5q
(Vahava et al. 1998), a mutation screen of
POU4F3
in affected members of
the Israeli family was undertaken and revealed an 8 bp deletion in exon 2.
This frameshift mutation results in a stop codon downstream of the dele-
tion with loss of the high affinity DNA-binding domain from the deduced
translation product. This mutation co-segregated with the
DFNA15
-linked
haplotype in all affected family members, with the exception of one indi-
vidual who is a phenocopy (Frydman et al. 2000; Vahava et al. 1998).
The 8 bp deletion mutation of
POU4F3
was not present in an older un-
affected individuals in the Israeli family, or in 114 unrelated, unaffected
control individuals of various Jewish ancestry from the ethnic populations
represented in members of the
DFNA15
family. No other
POU4F3
mutant
alleles have been found and the 8 bp deletion of
POU4F3
has not been
found in any other DFNA families. These data suggest that
DFNA15
may
not be a major contributor to progressive deafness in early and middle age,
but clearly is essential for maintenance of the auditory system in adult life.
