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 1

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(a) Pedigree drawing of the FHC family carrying the ACTC Ala295Ser mutat...
(a) Pedigree drawing of the FHC family carrying the ACTC Ala295Ser mutation. Individual numbers are given in italics, and symbols are defined as follows: squares, men; circles, women; diagonal slashes, deceased; open symbols, unaffected individuals; filled symbols, affected individuals fulfilling major diagnostic criteria; shaded symbols, affected individuals fulfilling minor diagnostic criteria; hatched symbols, excluded from linkage analyses because of hypertension. Alleles defined by the STR polymorphism within ACTC are shown in roman numerals (16). Thin bars indicate normal genotype of ACTC; thick bars indicate ACTC mutation segregating with allele 2. The genotype of individual I-3 was inferred from offspring. Individuals II-3 and II-8 have 2 children each who did not want to participate in this investigation. This may well influence the otherwise surprising observation that all individuals of the third generation carry the mutant allele. (b) Sequence of the ACTC wild-type and the G253→T mutated allele.