We identified the a-cardiac actin gene (ACTC) as a novel disease gene in a
pedigree suffering from familial hypertrophic cardiomyopathy (FHC). Linkage
analyses excluded all the previously reported FHC loci as possible disease
loci in the family studied, with lod scores varying between -2.5 and -6.0.
Further linkage analyses of plausible candidate genes highly expressed in
the adult human heart identified ACTC as the most likely disease gene, show
ing a maximal lod score of 3.6. Mutation analysis of ACTC revealed an Ala29
5Ser mutation in exon 5 close to 2 missense mutations recently described to
cause the inherited form of idiopathic dilated cardiomyopathy (IDC). ACTC
is the first sarcomeric gene described in which mutations are responsible f
or 2 different cardiomyopathies. We hypothesize that ACTC mutations affecti
ng sarcomere contraction lead to FHC and that mutations affecting force tra
nsmission from the sarcomere to the surrounding syncytium lead to IDC.