Genetics & Environmental Business Week

September 30, 2004


HEADLINE: STATENS SERUM INSTITUTE, COPENHAGEN;
Mutations influencing mRNA could play a role in hypertrophic cardiomyopathy

BODY:

Genetic and phenotypic characterization of mutations in myosin-binding
protein C (MYBPC3) have been studied in 81 families with familial hypertrophic
cardiomyopathy.

Scientists in Denmark report, "Mutations in the MYBPC3 gene, encoding the
sarcomere protein myosin-binding protein C, are among the most frequent causes
of autosomal dominant familial hypertrophic cardiomyopathy (FHC). We studied the
frequency, type, and pathogenetic mechanism of MYBPC3 mutations in an unselected
cohort of 81 FHC families, consecutively enrolled at a tertiary referral center.
"

P.S. Andersen and colleagues of the Statens Serum Institute in Copenhagen
reported, "Nine mutations, six of which were novel, were found in 10 (12.3%) of
the families using single-strand conformation polymorphism and DNA sequencing. A
frameshift mutation in exon 2 clearly suggests that haploinsufficiency is a
pathogenetic mechanism in FHC. In addition, splice site mutations in exon 6 and
intron 31, a deletion in exon 13, and a nonsense mutation in exon 25, all lead
to premature termination codons, most likely causing loss of function and
haploinsufficiency."

"Furthermore, there were two missense mutations (D228N and A833 T) and one
in-frame deletion (DeltaLys813). A considerable intrafamilial variation in
phenotypic expression of MYBPC3-based FHC was noted, and we suggest that
mutations influencing stability of mRNA could play a role in the variable
penetrance and expressivity of the disease, perhaps via partial
haploinsuffciency," they added.

Andersen and colleagues published their study in the European Journal of
Human Genetics (Genetic and phenotypic characterization of mutations in
myosin-binding protein C (MYBPC3) in 81 families with familial hypertrophic
cardiomyopathy: total or partial haploinsufficiency. Eur J Hum Genet,
2004;12(8):673-677).