Biology Reference
In-Depth Information
sclerosis is likely to result from an interplay between at least some or all of
these genetic, hormonal, infectious, and immunologic factors.
4.1 A Locus Associated with an Otosclerotic Phenotype
One important advance has been the mapping of a locus for otosclerotic
hearing loss (OTS) to chromosome 15q25-q26 in a single family from India
with no recorded consanguinity (Tomek et al. 1998) (Table 6.1). A some-
what higher degree of penetrance in this kindred facilitated the detection
of linkage, as only three of 16 family members who inherited the OTS-
linked haplotype did not have clinically detectable otosclerosis. The identi-
fication of a gene associated with otosclerotic hearing loss would provide
an important molecular foundation for delineating this complex process,
although mutations in
OTS
may not account for many, if not most, cases of
otosclerosis.
4.2 Osteogenesis Imperfecta (OI) and Hearing Loss
Osteogenesis imperfecta (OI; chromosome 7) is a syndrome known to cause
a stapes fixation phenotype similar to that of otosclerosis. OI is a dominant
disorder caused by mutations in the a1 or a2 subunits of type I collagen,
which result in abnormal bone remodeling and formation (Byers 1993). The
OI phenotype is variably expressed and includes brittle or deformed bones,
hyperextensible joints, and blue sclerae in addition to conductive hearing
loss. An allele association study demonstrated linkage disequilibrium
between otosclerosis and markers at the
COL1A1
locus encoding the a1
subunit of type I collagen (McKenna et al. 1998). The authors hypothesized
that otosclerosis may be associated with heterozygous null alleles of
COL1A1
that are similar to those found in mild cases of OI.
These results suggest models for the etiology of otosclerosis. One model
is that histologic otosclerosis is caused by a viral infection in individuals car-
rying heterozygous mutations in
COL1A1
,
OTS
, or other genes yet to be
identified. Good candidates would be genes encoding extracellular matrix
molecules, such as other collagens. The subsequent progression of otoscle-
rosis might then be affected by hormonal factors such as those associated
with pregnancy. The causal relationship between viral infection and oto-
sclerosis may be direct or indirect, involving immune or autoimmune
mechanisms that are triggered by the infection.
These first steps toward the identification of genetic loci associated with
otosclerosis provide an important foundation for testing these models.
Future identification of molecular genotypes at
COL1A1
and
OTS
will help
clarify the roles of other causative factors. The elucidation of complex
multigenic traits in other systems is just beginning to evolve, and otoscle-
rosis should be an excellent auditory model system in which to apply those
approaches.
