Biology Reference
In-Depth Information
or recessive locus, respectively. DFNA and DFNB loci have a numeric
suffix, a consecutively increasing Arabic number indicating the order
in which the DFNA, DFNB, or DFN locus was mapped (http://www.
gene.ucl.ac.uk/nomenclature/). This nomenclature reveals nothing about
the chromosomal address of the gene or the associated audiological phe-
notype, except in the case of X-linked DFN loci that map to the X chro-
mosome. After publication of a new DFN locus, the gene is given a unique
six-digit MIM number (see http://www3.ncbi.nlm.nih.gov/Omin/ or the
printed version (McKusick 1998)).
Although recessive mutations of deafness genes usually cause congeni-
tal profound deafness (Tables 6.1 and 6.2), dominant alleles, with a few
exceptions, are associated with progressive hearing loss. Mutations of
dosage-sensitive genes would be expected to be dominant via a mechanism
known as haploinsufficiency. Alternatively, the product of a dominant
mutant allele might “poison” the function of the wild-type gene product via
a dominant negative mechanism. For example, the function of a multimeric
complex normally comprised of wild-type gene products may be disrupted
by the incorporation of the product of a mutant allele of that gene.
Twenty-eight DFNB loci have been mapped, and six have now been iden-
tified:
DFNB1
,
DFNB2
,
DFNB3
,
DFNB4
,
DFNB9
and
DFNB21
. Thirty-
five DFNA loci have been mapped and ten have been identified that
map to nine loci:
DFNA1
,
DFNA2
,
DFNA3
,
DFNA5
,
DFNA8/12
,
DFNA9
,
DFNA11
,
DFNA13
and
DFNA15
(Table 6.4). The first part of this review
is primarily focused on those DFNA and DFNB loci that have been
identified.
Surprisingly, many of the DFNA and DFNB genes are expressed in
tissues other than the auditory system (Table 6.4), yet mutant alleles seem
only to cause nonsyndromic hearing loss. In some families thought pre-
liminarily to be segregating nonsyndromic hearing loss, there may well be
other clinical features that were missed initially and become obvious when
more is known about the tissue and developmental expression profiles of
the causative gene. Alternatively, a mutant phenotype may be restricted to
the auditory system because other tissues in which the gene is expressed
have functional redundancy for that particular gene product. Other gene
products with similar functions presumably compensate for disruption of
function of the mutated gene.
The rigor of proof of identification varies for the deafness genes that have
been identified to date. To demonstrate that a disease gene has been iden-
tified, a candidate gene must reside within the critical map interval of the
disease gene and, if fully penetrant, the mutant allele co-segregates with the
disease. Mutant alleles that alter protein sequence or expression pattern in
a biologically significant manner are not usually common polymorphisms,
and are absent in a random sampling of several hundred individuals.
However, a high carrier rate does not necessarily mean the variant is a
benign polymorphism. Some mutant alleles of disease genes have a high
