Biology Reference
In-Depth Information
encodes a protein, otoferlin, that is expressed predominantly in organ of
Corti postnatal inner hair cells. The deduced sequence is predicted to
encode three C2-like domains and suggests that otoferlin may be involved
in synaptic vesicle trafficking.
3.13 DFN Loci
About 1 to 3% of childhood nonsyndromic recessive deafness (NSRD) is
due to mutant alleles of genes that are sex- or X-linked (Fraser 1965;
Reardon et al. 1992). Sex-linked NSRD is clinically and genetically het-
erogeneous with five loci,
DFN1
,
DFN2
,
DFN3
,
DFN4
and
DFN6
, described
to date (Table 6.3). The nomenclature for sex-linked hearing loss is con-
fusing because gene symbols were assigned prior to genetic mapping and,
in the case of
DFN1
, before clinical evaluations revealed that affected
members have a form of syndromic hearing loss now referred to as Mohr-
Tranebjaerg syndrome, MTS.
The X-linked loci causing nonsyndromic hearing loss are discussed in
numerical order, including
DFN1
. To date, mutant alleles of
DFN1
,
DFN3
and
DFN6
are associated with more mild hearing loss, in comparison with
mutant alleles of
DFN2
and
DFN4
that cause profound childhood deafness.
3.14 DFN1 is Mohr-Tranebjaerg Syndrome
A Norwegian family was described that segregated X-linked nonsyndromic,
sensorineural, postlingual, progressive deafness. Because of the obvious
pattern of transmission from mothers to sons, the locus was assigned to the
X chromosome in this family and designated
DFN1
(Mohr and Mageroy
1960). Clinical re-evaluation of the affected members of this family in 1995
revealed that progressive hearing loss was one of the first presenting neuro-
logical deficits of a more generalized phenotype including progressive corti-
cal blindness, dystonia, spasticity and mental deterioration. As a result,
DFN1
was reclassified as syndromic deafness, but still designated
DFN1
and
called Mohr-Tranebjaerg syndrome, MTS (Tranebjaerg et al. 1995).
A clue to the identity of the
DFN1
gene came from a patient with a
contiguous deletion syndrome composed of X-linked immunodeficiency
agammaglobulinemia (XLA OMIM 300300), dystonia, and progressive sen-
sorineural hearing loss. The deletion was found to encompass five genes.
One of these genes is
BTK
, in which point mutations cause XLA (Vetrie
et al. 1993). The
DDP
(deafness dystonia peptide) gene was also deleted in
this patient and was a candidate for MTS. The coding region of
DDP
is
divided into two exons encoding a 97 amino acid peptide of 11 kDa. Two
different frameshift mutations in
DDP
were identified in the Norwegian
DFN1
pedigree and in an additional family segregating only deafness and
dystonia (Jin et al. 1996).
