This report describes cardiomyopathy, hypertrophic (postulated), RAS-related. Work done in flies using the Dmel\Ras85D gene implicates this gene family in the development of hypertrophic cardiomyopathy. The RAS proteins are GDP/GTP-binding proteins that act as intracellular signal transducers and are crucial players in many signaling networks affecting cell cycle progression, growth, migration, cytoskeletal changes, apoptosis, and senescence. Dmel\Ras85D is most closely related to KRAS, HRAS and NRAS; there are multiple other paralogous and orthologous genes in both species. Classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\Ras85D.
KRAS has been implicated in Costello syndrome (MIM:218040); cardiac abnormalities, including hypertrophic cardiomyopathy, are commonly seen in sufferers of this disease. Of the three human RAS GTPase genes, a tagged UAS construct of Hsap\HRAS has been introduced into flies, but has not been characterized.
Animals homozygous for loss-of-function alleles of Dmel\Ras85D die during the larval stage. A UAS-driven constitutively activated form of Dmel\Ras85D, when expressed in the heart, results in smaller heart chambers with reduced end-diastolic dimensions, heart wall thicknesses are two to three times those of controls, and abnormal cardiac morphology with myofiber disarray. The number of cells in the transgenic hearts is similar to that in wild-type, indicating that the increased wall thickness is the result of cardiomyocyte hypertrophy, not an increase in cell proliferation. Many physical and genetic interactions for Ras85D have been described; see below and in the gene report for Ras85D.
Originally defined as oncogenes, this RAS GTPase family is implicated in many forms of cancer. See the human disease model report 'cancer, multiple, RAS-related' (FBhh0000474) and related reports.
[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]
In response to stress and extracellular signals, the heart undergoes a process called cardiac hypertrophy during which cardiomyocytes increase in size. If untreated, cardiac hypertrophy can progress to overt heart failure that causes significant morbidity and mortality (FBrf0221950 and references cited therein).
The RAS proteins are members of a large superfamily of low-molecular-weight GTP-binding proteins. The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. Three members of the RAS family, HRAS, KRAS and NRAS, are found to be activated by mutation in human tumors. These three members are very closely related, having 85% amino acid sequence identity (Downward, 2003; pubmed:12509763).
Many to many: multiple paralogs and orthologs in both species.
Many to many: multiple paralogs and orthologs in both species.
Many to many: multiple paralogs and orthologs in both species.
