This report describes cardiomyopathy, hypertrophic (postulated), RAF-related. Work in mice and flies implicates the human gene RAF1 (or possibly a related human gene) in the development of hypertrophic cardiomyopathy. RAF1 encodes Raf-1 proto-oncogene, serine/threonine kinase, a MAP3K. There is one high-scoring fly ortholog, Raf, for which classical amorphic mutations, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. RAF1 is associated with a form of dilated cardiomyopathy in human (OMIM:615916, FBhh0000156) and with the diseases Noonan syndrome with multiple lentigines 2 (OMIM:611554, FBhh0000132) and Noonan syndrome 5 (OMIM:611553, FBhh0000131); see also the human disease model report 'cancer, multiple, RAF-related' (FBhh0000558). Dmel\Raf is orthologous to two additional human genes, ARAF and BRAF.
Multiple transgenic constructs of the human Hsap\RAF1 gene have been introduced into flies, including wild-type RAF1, gain-of-function RAF1, UAS and heat-shock promoter constructs, and genes carrying an N-terminal deletion. Constitutively active Hsap\RAF1 has been shown to cause symptoms of hypertrophic cardiomyopathy in flies, including decreased end diastolic lumen dimensions, abnormal cardiomyocyte fiber morphology, and increased heart wall thicknesses.
Animals homozygous for amorphic mutations of Dmel\Raf exhibit lethality in the late larval stage; imaginal discs are undeveloped. Embryos lacking all Dmel\Raf activity (derived from homozygous null germline clones in the mother and not rescued by paternal contribution) die in early embryogenesis. When targeted to the developing heart, both overexpression and RNAi-effected reduction of function result in cardiac defects. Many physical and genetic interactions have been described for Dmel\Raf; see below and in the gene report for Raf.
[updated Aug. 2020 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 OMIM: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).
RAF1 encodes a MAP3K serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade. [Gene Cards, RAF1; 2018.02.22]
Many to one: 3 human to 1 Drosophila; the other human genes are BRAF and ARAF.