Biology Reference
In-Depth Information
type
HDIA1
amino acids at the carboxy terminus of the protein (Lynch
et al. 1997).
The function of
HDIA1
(
Diaphanous
) in the auditory system, as well as
the pathophysiology of the
HDIA1
mutation, are not known.
HDIA1
is a
member of the formin family of genes that are important for normal cytoki-
nesis and establishment of cell polarity. Functional clues about
HDIA1
may
come from the fruit fly,
Drosophila melanogaster
, where a null allele of
diaphanous
is a pupal-lethal, a hypomorphic allele causes male sterility, and
a weak allele results in polyploid cells in the central nervous system. It has
been suggested that human
diaphanous
interacts with profilin to regulate
actin filament formation, thereby affecting the intricate actin cytoskeleton
of hair cells (Lynch et al. 1997). Any model for the function of human
diaphanous in the inner ear should incorporate the delayed onset and pro-
gressive nature of the hearing loss associated with the
HDIA1
mutation
observed in the Costa Rican kindred.
3.3 DFNA2
The
DFNA2
locus was mapped to 1p34 in several large families from
Indonesia, the United States, Belgium and the Netherlands that were seg-
regating dominantly inherited, progressive hearing loss (Coucke et al. 1994;
Van Camp et al. 1997b). This chromosomal interval contains two good deaf-
ness candidate genes, one encoding a potassium channel (
KCNQ4
) and the
other a gap junction family member,
GJB3
(connexin 31,
Cx31
). Subse-
quently, affected individuals in two small Chinese families with hearing loss
were reported to have dominant mutations in
GJB3
, R180X and E183K, a
nonsense mutation and a missense mutation, respectively. These postulated
dominant mutations do not co-segregate perfectly with the hearing loss in
two small Chinese pedigrees (Xia et al. 1998). For example, an unexplained
nonpenetrant individual segregating the R180X mutation indicates that the
R180X is not the pathogenic mutation and/or that there are other factors
modifying the hearing-loss phenotype. Therefore, the genetic mechanism of
dominant
GJB3
mutations such as R180X cannot be explained by a simple
dominant mutation at this single locus.
Unfortunately, it is not possible to perform linkage analysis studies to
corroborate these conclusions. The two Chinese pedigrees with a total of
four affected individuals are too small to achieve a statistically significant
Lod score. Nevertheless, recessive mutant alleles of
GJB3
do appear to be
associated with hearing loss. Compound heterozygous mutant alleles of
GJB3
(R180X and E183K) were reported to co-segregate with probable
recessive hearing loss in two small Chinese pedigrees (Liu et al. 2000).
However, the recessive deafness mutations of
GJB3
in this study also lack
corroborating linkage analysis.
DFNA2
is an example of locus heterogeneity in that mutant alleles of
two closely linked genes,
GJB3
and
KCNQ4
, appear to be associated with
