Hypertrophic cardiomyopathy, profilin-related, has been modeled in Drosophila using the fly profilin gene chic. Profilins are small, multifunctional actin-binding proteins; they play a role in actin dynamics by regulating actin polymerization in response to extracellular signals. Work in mouse and rat supports the hypothesis that PFN1, the vertebrate cardiac-specific profilin, has a role in the development of hypertrophic cardiomyopathy. There are four profilin genes in human, PFN1, PFN2, PFN3, and PFN4; chic is the only profilin gene in flies. Classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for chic.
Multiple UAS constructs of the human Hsap\PFN1 gene have been introduced into flies, but have not been used in the context of this disease model. The human PFN1 gene is also implicated in amyotrophic lateral sclerosis 18; variants of Hsap\PFN1 implicated in ALS18 have been studied in flies (see FBhh0000023).
Animals homozygous for amorphic mutations of Dmel\chic die during the embryonic stage; mutant embryos exhibit developmental and neuroanatomy defects. Heart-specific overexpression of chic results in significantly larger heart tube dimensions in adults. Muscle-specific overexpression results in elongated sarcomeres, myofibrillar disorganization, and sarcomeric disarray; these cellular phenotypes correlate with phenotypes of impaired muscle function (flight and climbing in adults). Many physical and genetic interactions of Dmel\chic have been described; see below and in the chic gene report.
Note that there is another example of a connection between a fly model of cardiomyopathy and a gene implicated in amyotrophic lateral sclerosis: see FBhh0000756 and MIM:600543 (ALS19).
[updated May 2019 by FlyBase; FBrf0222196]
Familial hypertrophic cardiomyopathy is a heart condition characterized by thickening (hypertrophy) of cardiac muscle. Thickening usually occurs in the interventricular septum, the muscular wall that separates the left ventricle from the right ventricle. Cardiac hypertrophy often begins in adolescence or young adulthood, although it can develop at any time throughout life. The symptoms are variable, even within the same family. While most people this condition are symptom-free or have only mild symptoms, hypertrophic cardiomyopathy can cause abnormal heart rhythms (arrhythmias) that may be life threatening. People with familial hypertrophic cardiomyopathy have an increased risk of sudden death, even if they have no other symptoms of the condition. A small number of affected individuals develop potentially fatal heart failure, which may require heart transplantation. [from Genetics Home Reference, familial hypertrophic cardiomyopathy; 2016.10.13]
Hypertrophic cardiomyopathy in early stages produces a presystolic gallop due to an atrial heart sound, and EKG changes of ventricular hypertrophy. Progressive ventricular outflow obstruction may cause palpitation associated with arrhythmia, congestive heart failure, and sudden death. Hypertrophic cardiomyopathy accounts for a significant number (exceeding 25% in one study) of sudden deaths of young athletes. [from MIM:192600; 2016.10.28]
Many to one: 3 profilin genes in human, PFN4, PFN1, and PFN2 show similarity to the Drosophila profilin, chic.
Low- to moderate-scoring ortholog of human PFN4, PFN1, and PFN2; Dmel\chic shares 28% identity and 42% similarity with PFN1 and PFN4.
