Biology Reference
In-Depth Information
dimerize with itself (Weil et al. 1997), and therefore this allele may be dom-
inant because its gene product can interact with wild-type myosin VIIA to
form a defective dimer (Fig. 6.4). Some functional dimers would be pre-
dicted to form between wild-type myosin VIIA polypeptides, leading to a
milder hearing loss phenotype in comparison with the profound congenital
deafness associated with homozygosity for recessive alleles causing total
loss of functional MYO7A.
3.10.4 Multiple Alleles of
MYO7A
There are over fifty mutations of
MYO7A
that give rise to a spectrum of
phenotypes (Adato et al. 1997; Levy et al. 1997; Liu et al. 1998; Weston et
al. 1996). Mutations that cause nonsyndromic recessive deafness,
DFNB2
,
and Usher syndrome 1B are distributed across the coding region of
MYO7A
(Fig. 6.4). Except for the
DFNA11
mutation in the coiled-coil
domain of
MYO7A
, there is no obvious pattern of mutation location or
mutation type, (missense, nonsense, frameshift, etc.) that would predict
whether a particular allele will cause hearing loss that is nonsyndromic, or
hearing loss that is associated with retinitis pigmentosa. If phenotypic vari-
ability is not entirely attributable to allelic heterogeneity of
MYO7A
, is it
the genetic background that is contributing to the pleiotropic phenotype?
This question is clinically important because identification of the modifier
gene(s) that permits or prevents blindness should be helpful in devising
therapeutic strategies to forestall the progressive blindness associated with
type 1B Usher's syndrome.
3.11 DFNB3
Mapping genes for recessive hearing loss can be more easily accomplished
in remote populations where there is a probable founder effect.
DFNB3
was first mapped in the village of Bengkala on the island of Bali, Indone-
sia (Friedman et al. 1995; Winata et al. 1995). There were 24 deaf males and
24 deaf females living in this village who shared a unique sign language with
one another and with the other 2,206 hearing members of the village
(Friedman et al. 2000; Hinnant 2000). Affected individuals cannot detect
sound at levels as high as 90 dB at any tested frequency. Formal vestibular
testing has not been performed, but some affected individuals describe
balance problems and dizziness when their eyes are closed, suggesting the
presence of vestibular dysfunction.
In a genome-wide screen,
DFNB3
was one of the first human disease
genes to be localized using a homozygosity mapping strategy (Friedman
et al. 1995). The deafness segregating in Bengkala was mapped to the
pericentromeric region of chromosome 17 (Friedman et al. 1995), and the
location of
DFNB3
was subsequently refined to a 4 to 5 cM region on chro-
