Biology Reference
In-Depth Information
DDP
is expressed at high levels in the fetal and adult brain, as well as in
many other cell types. Insight into the role that
DDP
plays in vertebrate
neurological development and in auditory function has come from charac-
terization of the
DDP
orthologues (Tim8p, Tim9p, Tim10p, Tim12p and
Tim13p) in the yeast
Saccharomyces pombe
. Tim8p shares 49% identity and
60% similarity over 63 amino acids with human
DDP
. DDP, like Tim8p, is
a nuclear-encoded mitochondrial protein that mediates import of metabo-
lites from the cytoplasm into the mitchondrial inner membrane (Koehler et
al. 1999).
3.15 DFN2
DFN2
was mapped in a large British family segregating X-linked profound
congenital sensorineural hearing loss. The deafness phenotype in this family
was first tested for linkage to markers near
DFN3
and
DFN4
, since these
loci had already been mapped. There were meiotic recombinations of the
hearing loss phenotype with
DFN3
-linked markers in affected males and
carrier females, some of whom had mild to moderate hearing loss.
DFN3
could thus be excluded as the causative locus and, similarly, hearing loss
was shown to not be linked to the
DFN4
interval or to the X-linked Alport's
syndrome locus (
COL4A5
, Fig. 6.1) (Tyson et al. 1996). A screen of X-
linked markers was undertaken and a new locus,
DFN2
, was mapped to
Xq22 in this family.
DFN2
is yet to be identified.
3.16 DFN3
Many families with X-linked progressive mixed hearing loss have been
described. Affected individuals typically have fixation of the stapes foot-
plate, and a brisk flow of perilymphatic fluid from the vestibule (known as
a “perilymphatic gusher”) is encountered when the stapes footplate is
opened during the stapedectomy procedure to correct the conductive
hearing loss (Cremers et al. 1985; Nance et al. 1971). Families segregating
X-linked sensorineural hearing loss without a conductive component also
map to
DFN3
. Computed tomography (CT) scanning of temporal bones
and inner ears have revealed associated osseous defects, which have been
proposed to be pathognomonic for
DFN3
mutations (Bach et al. 1992;
Phelps et al. 1991), and serve as a warning to surgeons contemplating
corrective stapes surgery.
The mixed hearing loss was mapped to Xq21.1 by linkage analyses,
cytologically detectable deletions and overlapping microdeletions, and this
locus was designated
DFN3
(Huber et al. 1994). Unlike many other regions
of the X-chromosome, cytologically detectable nullisomy for Xq21 is com-
patible with life and is usually associated with hearing loss. However, there
are a few normal-hearing patients with a deletion of Xq21, an inconsistency
