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effects of homozygous null alleles of GJB2 in humans, in whom GJB2 does
not appear to be essential for viability or development. It is possible that
mutant mouse missense alleles may not cause a lethal phenotype in their
mouse orthologues, in which case a search for modifying genes would be
possible. These and other mouse models would also be useful for electro-
physiologic and histopathologic evaluations of the effects of connexin
mutations in the auditory system, studies that are difficult to carry out in
humans.
3.10 DFNB2, DFNA11 and USH1B are
the Same Locus
Nonsyndromic recessive deafness associated with partially penetrant
vestibular dysfunction was initially mapped to 11q by linkage analysis in a
consanguineous family from South Tunisia (Guilford et al. 1994a). The loca-
tion was subsequently refined by homozgosity mapping to 11q13.5
(Guilford et al. 1994a), and the locus was designated DFNB2 (Fig. 6.1 and
Table 6.2). Since the Tunisian family is consanguineous, markers in the
region closely flanking DFNB2 are expected to be homozygous by shared
descent from an ancestral allele (Lander and Botstein 1987). All 24 affected
individuals of this family were homozygous for the DFNB2 -linked haplo-
type consisting of seven markers across the 6-cM interval on 11q13.5. Het-
erozygosity for markers flanking this interval demarcated the DFNB2
critical region. Thirty-one of 32 unaffected members of the family had one
or no copies of the DFNB2 -linked haplotype, whereas one normal-hearing
person who was twenty-five years old was homozygous for the DFNB2 -
linked haplotype. The possibility of reduced penetrance of DFNB2 is sup-
ported by the observation of highly variable severity (ranging from mild to
profound SNHL) and age of onset (ranging from congenital to onset at 16
years of age) of hearing loss in the affected members of the Tunisian
kindred.
3.10.1 Shaker 1 is the Orthologue of DFNB2 , DFNA11 and USH1B
Usher syndrome is a clinically and genetically heterogeneous disorder char-
acterized by autosomal recessive transmission of sensorineural hearing loss
and retinitis pigmentosa (see Section 5.4.2). One particular subtype of
Usher syndrome, type 1B, was mapped to human chromosome region
11q13.5 (Kimberling et al. 1992). The known genes located on 11q13.5 share
conserved linkage with their homologues on part of mouse chromosome 7
containing the interval to which the shaker 1 ( sh-1 ) mutation maps (Evans
et al. 1993). Homozygous sh-1 mice demonstrate a phenotype of circling
behavior and neurosensory deafness, therefore presenting an excellent can-
didate gene for hereditary deafness disorders in humans (Lyons and Searle
1989).
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