α-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy
Jens Mogensen, … , Ulrik Baandrup, Anders D. Børglum
Jens Mogensen, … , Ulrik Baandrup, Anders D. Børglum
Published May 15, 1999
Citation Information: J Clin Invest. 1999;103(10):R39-R43. https://doi.org/10.1172/JCI6460.
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α-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy

Abstract

We identified the α-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, showing a maximal lod score of 3.6. Mutation analysis of ACTC revealed an Ala295Ser 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 for 2 different cardiomyopathies. We hypothesize that ACTC mutations affecting sarcomere contraction lead to FHC and that mutations affecting force transmission from the sarcomere to the surrounding syncytium lead to IDC.

Authors

Jens Mogensen, Ib C. Klausen, Anders K. Pedersen, Henrik Egeblad, Peter Bross, Torben A. Kruse, Niels Gregersen, Peter S. Hansen, Ulrik Baandrup, Anders D. Børglum

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Figure 3

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Schematic stereo representation of the actin monomer based on the crysta...
Schematic stereo representation of the actin monomer based on the crystal structure of actin (33). Putative binding sites to myosin are in yellow (28). The Ala295 amino acid mutated in the FHC family is shown in red and localized at the actin surface close to a possible myosin-binding site. The 2 amino acids mutated in IDC (Arg312 and Glu361) are shown in purple. The amino acid differences between α-cardiac actin and the γ-enteric actin expressed in the transgenetically modified ACTC knockout mouse are demonstrated in green. The figure was prepared using the protein database (34).