Biology Reference
In-Depth Information
to map
DFNA8
and
DFNA12
(Verhoeven et al. 1998). Two missense muta-
tions, L1820F and G1824D, in exon 17 were found in the Belgian family and
a missense mutation, Y1870C, was found in exon 18 in the Austrian family.
Eighteen affected members of the Belgian family had the two adjacent mis-
sense mutations, and eight affected members in the Austrian family had the
Y1870C mutation. These mutations were absent in the unaffected family
members and in 100 representative normal controls, thus ruling them out
as common polymorphisms.
Dominant mutant alleles of
TECTA
may account for the hearing-loss
phenotype either through a dominant negative mechanism in which defec-
tive a-tectorin disrupts the structure of the tectorial membrane, and/or hap-
loinsufficiency of
TECTA
may occur as a result of destabilization of mutant
TECTA
mRNA (Verhoeven et al. 1998). Mouse models in which the mis-
sense mutations of
TECTA
are introduced into
Tecta
may help to explain
the molecular pathology of these
TECTA
mutations. Like a-tectorin, mouse
b-tectorin encoded by
Tectb
is a major tectorial membrane protein.
Tectb
maps to mouse Chromosome 19 in a region homologous to human 10q25
(Kim et al. 1998) and is a good candidate gene for a deafness locus.
3.6.1
DFNB21
and
TECTA
Prelingual, recessive, sensorineural, nonsyndromic deafness
DFNB21
seg-
regating in a single family was reported to be linked to chromosome
11q23-25 (Mustapha et al. 1999).
TECTA
was screened for mutations and
affected individuals were found to be homozygous for a donor splice site
mutation that truncates
TECTA
by 55%. Heterozygous carriers of this
recessive mutation have normal hearing. Mutations of
TECTA
can be
either dominant or recessive (Mustapha et al. 1999), indicating that the
dominant
TECTA
mutations are unlikely to be null alleles, but rather have
a dominant negative mode of action.
3.7 DFNA9
Dominant, progressive hearing loss was mapped to 14q12-q13 in a single
family and is designated
DFNA9
(Manolis et al. 1996). Two other
DFNA9
families were subsequently identified (Robertson et al. 1998). Hearing loss
in these
DFNA9
families begins at 20 to 40 years of age, initially affecting
high frequencies and progressing to profound deafness across all fre-
quencies by ages 40 to 50. Affected members of the
DFNA9
family have
vestibular dysfunction, but with reduced penetrance and variable expres-
sion. Temporal bones of members of a
DFNA9
family contained acidophilic
deposits in the cochlear nerve channels, the spiral limbus and the spiral
ligament (Khetarpal 1993; Khetarpal et al. 1991). The identity and patho-
genic significance of these deposits are unknown.
