Wm. Franz et al., Association of nonsense mutation of dystrophin gene with disruption of sarcoglycan complex in X-linked dilated cardiomyopathy, LANCET, 355(9217), 2000, pp. 1781-1785
Citations number
33
Categorie Soggetti
General & Internal Medicine","Medical Research General Topics
Background In a systematic analysis of inherited forms of cardiomyopathy, w
e previously identified a family with X-linked dilated cardiomyopathy chara
cterised by a mutation in the rod region of dystrophin. We have now attempt
ed to eludicate the genetic mechanism involved in this disease, as well as
the role of dystrophin-associated glycoproteins.
Methods The affected dystrophin epitope, which lacks binding to the dys-1 a
ntibody, was analysed by single-strand conformation polymorphism analysis,
reverse-transcription PCR, and DNA sequencing. Effects on dystrophin-associ
ated glycoproteins were studied by immunohistochemistry and western blottin
g.
Findings A translation-termination mutation (C4148T) in exon 29 of the dyst
rophin gene was found in all affected family members. Alternative splicing
rescued the reading frame and led to the expression of a dystrophin molecul
e lacking 50 aminoacids both in cardiac and skeletal muscle. Immunohistoche
mical analysis of the dystrophin-associated proteins revealed a reduction o
f beta-sarcoglycan and delta-sarcoglycan in the sarcolemma of cardiac muscl
e but not skeletal muscle tissue. However, western blotting revealed simila
r amounts of sarcoglycan subunits in both tissues.
Interpretation The molecular mechanism of this subtype of X-linked cardiomy
opathy may be explained by a conformational change in exon-29-deleted dystr
ophin, resulting in disruption of the sarcoglycan assembly in heart muscle
but not skeletal muscle.