Human Molecular Genetics, Vol 8, 481-492, Copyright © 1999 by Oxford University Press
CL Winchester, RK Ferrier, A Sermoni, BJ Clark and KJ Johnson
The pathogenic mechanisms underlying myotonic dystrophy (DM), which results
from a (CTG) n repeat expansion mutation in the 3'-untranslated region
(3'-UTR) of the myotonic dystrophy protein kinase gene ( DMPK ), remain
obscure. The multisystemic nature and variable expressivity of the symptoms
are unlikely to be explained by a defect in this gene alone. However, the
location of the DM-associated (CTG) n repeat in the promoter region of
SIX5, immediately downstream of DMPK, implicates it as a second candidate
with a pathological role in DM. We hypothesize that dysfunction of SIX5,
which is homologous to the Drosophila eye development gene sine oculis ( so
), is primarily responsible for the ophthalmic features of DM. We report an
expression pattern for SIX5 in the normal adult eye that matches the sites
of the ocular pathology in DM. SIX5 transcripts were detected in the adult
corneal epithelium and endothelium, lens epithelium, ciliary body
epithelia, cellular layers of the retina and the sclera. SIX5 expression
was not detected in fetal eyes. We also report a restricted but partially
overlapping expression pattern for DMPK transcripts and DMPK protein in
normal fetal and adult eyes. DMPK transcripts were detected in fetal eyes
and in adult conjunctival and corneal epithelia, uvea, cellular layers of
the retina, optic nerve and in the sclera. DMPK protein was detected in the
adult retina, conjunctival and ciliary body epithelia and in the smooth
muscle of the ciliary body, pupillary sphincter and uveal blood vessels. We
propose that the expression patterns of these two genes indicate their
relative contribution to the ophthalmological dysfunction seen in DM.
Furthermore, the expression of SIX5 and not DMPK in the adult lens
implicates a role for SIX5 dysfunction in the development of adult onset
cataracts, the most frequently occurring eye phenotype in DM.
ARTICLES
Characterization of the expression of DMPK and SIX5 in the human eye and implications for pathogenesis in myotonic dystrophy
Division of Molecular Genetics, Institute of Biomedical and Life Sciences, University of Glasgow, Anderson College, 56 Dumbarton Road, Glasgow G11 6NU, UK.
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