Biology Reference
In-Depth Information
carrier frequency. For example, among Caucasians, the carrier frequency is
2 to 3% for the DF508 mutant allele of
CFTR
, the gene for cystic fibrosis
(Morral et al. 1994), and among Ashkenazi Jews there is a carrier frequency
of 4% for the 167delT mutant allele of
GJB2
(Morell et al. 1998).
Other types of observations strengthen the argument that a disease gene
has indeed been identified, although these issues sometimes cannot be
addressed easily. For example, animal models with a mutation in the ortho-
logue of the human gene that approximates the human disease phenotype
can be instrumental in understanding the pathophysiology. Moreover, cor-
rection of the mutant phenotype in an animal model by introducing the
wild-type gene is a definitive demonstration that the disease gene has been
correctly identified (Probst et al. 1998).
Finally, there are now cautionary tales suggesting that assignment of
the “nonsyndromic” classification may be misapplied in the absence of
thorough clinical data (Baldwin et al. 1995; Tranebjaerg et al. 1995) and it
is certainly premature if the most common syndromes are not ruled out.
The “nonsyndromic” designation for a mutant allele causing deafness
should be considered tentative until the gene is identified and its spatial
expression pattern is known. For nonsyndromic deafness genes that are
expressed in tissues other than the auditory system, there may be associ-
ated subclinical features that were initially unnoticed.
3.2 DFNA1
3.2.1 Genetics
In an extended Costa Rican family, autosomal-dominant, progressive sen-
sorineural hearing loss was inherited from two affected brothers who
migrated to Costa Rica from Spain in the eighteenth century. Low-
frequency hearing begins to be lost in the first decade, with profound losses
at all frequencies occurring by age 30 (Lalwani et al. 1998; Leon et al. 1981).
The causative gene,
DFNA1
, was found to be linked to markers defining a
~7 cM critical interval on 5q31 (Leon et al. 1992). This was the first auto-
somal nonsyndromic hearing loss gene to be mapped.
3.2.2
Diaphanous
is
DFNA1
DFNA1
was positionally cloned and identified as the human homologue of
the Drosophila
diaphanous
gene (Lynch et al. 1997). Human
diaphanous
,
HDIA1
, is composed of 26 exons encoding a 140 kDa protein (E. Lynch,
personal communication). A G-to-T substitution in the consensus splice
donor site of the penultimate exon was found in all 78 affected members
of the Costa Rican family, but not in 330 normal-hearing members of this
family. The G-to-T substitution results in aberrant splicing of exon 25 at a
cryptic site 4 nucleotides into the intron. Splicing at this cryptic site causes
a frameshift with substitution of 21 aberrant amino acids for the 32 wild-
