Biology Reference
In-Depth Information
cardiogram. The frequency of this syndrome, also known as cardioauditory
syndrome or surdocardiac syndrome, is about 0.25% among those with con-
genital profound deafness (Gorlin et al. 1995). Although rare, the impor-
tance of this syndrome lies in the high mortality rate if undetected and
untreated; approximately 70% may die between early infancy and 14 years
of age due to fatal cardiac arrhythmias (Gorlin et al. 1995).
The fainting spells may range from pallor and sweaty palms to loss of
consciousness for up to several minutes. The episodes may begin anytime
after infancy, but usually appear between three and five years of age. There-
fore the hearing loss is present and detectable before the diagnosis is sug-
gested by the fainting spells. Early detection is critical since antiarrhthmic
therapy including beta-adrenergic blocking agents improves the prognosis
(Ackerman 1998).
5.6.2 Jervell and Lange-Nielsen Syndrome is Genetically
Heterogeneous
Autosomal recessive inheritance has been well established by frequent
observations of parental consanguinity. Fraser et al. (1964) noted that
heterozygotes may exhibit prolongation of the Q-T interval. Neyroud
et al. (1997) analyzed four consanguinous families with Jervell and
Lange-Nielsen syndrome for linkage to genes causing long-QT syndrome
(without deafness), and found linkage to markers on chromosome 11p15.5
near the
KVLQT1
locus previously demonstrated to be associated with
dominant long-QT (Romano-Ward) syndrome. They demonstrated a
homozygous 8-bp insertion event at the site of a 7-bp deletion of wild-type
DNA in the C-terminal portion of the mutant allele, causing a +1-bp
frameshift that is predicted to result in premature termination.
KVLQT1
is expressed in the stria vascularis of the mouse inner ear (Neyroud et al.
1997), as would be predicted from the observed temporal bone pathology
suggesting a primary defect in the stria vascularis and endolymph home-
ostasis (Friedmann et al. 1968; Friedmann et al. 1966).
The existence of an additional JLNS locus was indicated by the identifi-
cation of two families that were not linked to
KVLQT1
(Schulze-Bahr et
al. 1997). JLNS in these families was shown to be associated with mutations
in
KCNE1
(chromosome 21q22.1-q22.2) (Schulze-Bahr et al. 1997), which
encodes a transmembrane protein known to associate with the
KVLQT1
gene product to form the slow component of the delayed-rectifier potas-
sium channel.
KVLQT1
encodes the alpha subunit and
KCNE1
encodes
the beta subunit, IsK, of this channel. Ion-channel beta subunits are known
to be ancillary proteins important for gating kinetics and stabilization of
heteromultimeric channel complexes. Previous work had demonstrated
expression of
KCNE1
on the endolymphatic surface of marginal cells in the
stria vascularis (Sakagami et al. 1991), again consistent with a primary
defect in the stria and endolymphatic homeostasis.
