Biology Reference
In-Depth Information
tial for transducing the physical stimulus of sound within the cochlea to
an electrical stimulus transmitted to the auditory nerve. The very short
stereocilia may explain the lack of hearing in
shaker 2
mice.
3.11.3 Mutations of Human
MYO15
Cause Deafness
Identification of
shaker 2
as
Myo15
triggered a search for
MYO15
mutations
in
DFNB3
families. The structure of
MYO15
was determined by sequencing
three overlapping cosmid clones corresponding to approximately 90 kb of
contiguous genomic DNA. The predicted 66 exons of
MYO15
were identi-
fied and confirmed by sequencing human
MYO15
cDNA synthesized from
human fetal inner ear, adult brain and pituitary gland mRNA (Liang et al.
1999). Genomic DNA encoding
MYO15
was sequenced from probands of
the three
DFNB3
families previously described. Two missense mutations
and one nonsense mutation in
MYO15
were identified (Fig. 6.4), and each of
the three mutations co-segregated with the deafness phenotype in the three
DFNB3
families (Wang et al. 1998).
Many questions remain about the roles of myosin XV, as well as myosin
VI and myosin VIIA, in the auditory and vestibular systems and in the
epidemiology of deafness. What are the other proteins that interact with
myosin XV and/or are transported within the cell by myosin XV? The
identification of myosin XV protein partners will be helpful in illumina-
tion of the function of myosin XV, and they will be good candidates for
other hearing impairment genes. Surprisingly, myosin XV is abundantly
expressed in the anterior pituitary gland, although there is no obvious
pituitary phenotype in deaf individuals homozygous for mutant alleles of
MYO15
. It is possible that there is functional redundancy for myosin XV
in the pituitary gland, where other proteins may be able to compensate for
the loss of functional myosin XV.
Although the phenotype of
shaker 2
suggests a role for myosin XV in
maintaining the cytoskeleton of stereocilia in hair cells, nothing is known
with confidence about the specific function of this novel unconventional
myosin. However,
Myo15
in inner ear hair cells is immunolocalized to the
cuticular plate and to the tops of stereocilia (Liang et al. 1999). Based on
its location at the top of hair cell stereocilia by electron microscopy, we
speculate that
Myo15
is part of the adaptation motor that is responsible
for regulating tip link tension and gating hair cell mechanotransduction
channels (Bechara Kachar, personal communication).
3.12 DFNB9
In a large Lebanese family, a novel gene responsible for recessive, sen-
sorineural, nonsyndromic deafness was mapped to 2p22-23 (Chaib et al.
1996a). Deafness was profound and congenital. Using a candidate gene
approach, a mutation in
OTOF
was identified (Yasunaga et al. 1999).
OTOF
