Biology Reference
In-Depth Information
Mondini cochlear deformity was a common, but not uniform, radiologic
feature of Pendred syndrome (Phelps et al. 1998). In contrast, enlargement
of the endolymphatic sac and duct in association with a large vestibular
aqueduct was observed in all 20 patients examined by MRI (Phelps et al.
1998). Several different surgical therapies designed to alter the structure
and physiology of the endolymphatic system have not been successful
at preventing progression of sensorineural hearing loss associated with
enlarged vestibular aqueducts (Jackler et al. 1988; Wilson et al. 1997).
5.2.2 Genetics of Pendred Syndrome
Pendred syndrome is transmitted in an autosomal-recessive pattern
(Fraser 1965; Fraser 1960) and was mapped to chromosome 7q31 in a region
known also to contain the nonsyndromic recessive deafness locus
DFNB4
(Baldwin et al. 1995; Coyle et al. 1996; Sheffield et al. 1996). Everett et al.
(1997) identified the Pendred syndrome gene,
PDS
, by a positional cloning
strategy. Northern analysis demonstrated significant expression of
PDS
in
thyroid tissue. Cochlear tissue was not included in the analysis, although it
was reported that PCR analyses of a human fetal cochlear cDNA library
detected the presence of
PDS
sequences.
PDS
was shown to be a novel
gene whose predicted protein, pendrin, shares homology to a family of tran-
smembrane proteins that appear to be sulfate transporters (Everett et al.
1997) (Fig. 6.6). However, the expression of human pendrin in
Xenopus
oocytes is associated with transport of iodine and chloride, but not sulfate
(Scott et al. 1998). Similar results were obtained in a second expression
system using a baculovirus vector and Sf9 host cells (Scott et al. 1998).
Everett et al. (1997) described three different
PDS
mutations, each of
which appears to act via a loss-of-function mechanism in Pendred syn-
drome. Two reports published together in 1998 further expanded the spec-
trum of known
PDS
mutations in Pendred syndrome (Fig. 6.6). Van Hauwe
et al. (1998) used genomic exon sequencing to identify
PDS
mutations in
fourteen of fourteen Pendred syndrome families examined from seven dif-
ferent countries. The results were noteworthly for the identification of two
frequent missense mutations, of which one or both were present in nine of
the fourteen families. Coyle et al. (1998) used SSCP to detect
PDS
muta-
tions in 56 kindreds with features suggestive of Pendred syndrome. They
identified and characterized one splice site and three missense mutations
that together accounted for 74% of the detected mutations. They con-
cluded, on the basis of analyses demonstrating common linked haplotypes,
that common founders were the likely source of the common mutations
(Coyle et al. 1998). The demonstration of common mutations by both
groups should facilitate the molecular diagnosis of Pendred syndrome, since
Pendred's syndrome is often difficult to diagnose clinically, and is probably
underascertained (Reardon et al. 1997).
