This report describes cardiomyopathy, dilated (postulated), EGFR/ERBB-related. Work done in Drosophila using the fly ru and Egfr genes implicates the EGFR gene family in the development of dilated cardiomyopathy. The EGFR gene encodes a transmembrane receptor kinase that spans the cell membrane and is activated by a number of external ligands; activation of EGFR initiates several signal transduction cascades, leading to DNA synthesis and cell proliferation. There are 3 closely related genes in human, ERBB4, ERBB3 and ERBB2. In Drosophila, Dmel\Egfr is the closest ortholog to all 4 human genes. Classical amorphic and hypomorphic alleles, constitutively active alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\Egfr.
The human Hsap\EGFR gene has been introduced into flies, but has not been used in the context of this gene model.
In Drosophila, characterization of a small deficiency with a phenotype comparable to dilated cardiomyopathy resulted in the identification of Dmel\ru (aka rho3) as the causative gene. Partial loss-of-function mutations of ru result in recessive cardiac phenotypes; deletion and amorphic mutations have dominant cardiac phenotypes. Since Dmel\ru was known to affect processing of Spitz and subsequent EGFR signaling, the Drosophila genes spi and Egfr were characterized for cardiac phenotypes and for genetic interactions impacting the ru cardiac phenotype. Overexpression of either rescues the ru cardiac phenotype; loss-of-function mutations in both exhibit cardiac phenotypes comparable to dilated cardiomyopathy. Post-developmental expression of a dominant-negative allele of Dmel\Egfr results in a progressive deterioration in cardiac function, suggesting that rhomboid-EGFR signaling participates in maintenance of adult cardiac function.
A constitutively activated form of Dmel\Egfr, expressed in the heart, has been used to model hypertrophic cardiomyopathy in flies; see the human disease model 'cardiomyopathy, hypertrophic (postulated), EGFR/ERBB-related' (FBhh0000756). The human EGFR gene has been implicated in multiple forms of cancer. See the human disease model report 'cancer, multiple, EGFR-related' (FBhh0000398) and related reports.
[updated May 2019 by FlyBase; FBrf0222196]
Nonsyndromic isolated dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and systolic dysfunction, a reduction in the myocardial force of contraction. DCM usually presents with any one of the following: (1) Heart failure with symptoms of congestion (edema, orthopnea, paroxysmal nocturnal dyspnea) and/or reduced cardiac output (fatigue, dyspnea on exertion); (2) arrhythmias and/or conduction system disease; (3) thromboembolic disease (from left ventricular mural thrombus) including stroke. [from Dilated Cardiomyopathy Overview, pubmed:20301486 2016.01.26]
Dilated cardiomyopathy (CMD) is characterized by cardiac dilatation and reduced systolic function. CMD is the most frequent form of cardiomyopathy and accounts for more than half of all cardiac transplantations performed in patients between 1 and 10 years of age. A heritable pattern is present in 20 to 30% of cases. Most familial CMD pedigrees show an autosomal dominant pattern of inheritance, usually presenting in the second or third decade of life (summary by Levitas et al., 2010, pubmed:20551992). [from MIM:115200, 2016.01.27]
ERBB2 signaling is a chemotherapy target for some cancers; treatment has been associated with increased risk of dilated cardiomyopathy (FBrf0210954; references cited therein).
The human rhomboid-like genes (such as RHBDL1 and RHBDL2) encode intramembrane serine proteases containing several transmembrane domains; they are involved in signalling in the Spitz/epidermal growth factor receptor/mitogen-activated protein kinase pathway. [from Gene Cards, RHBDL1; 2019.04.11]
Epidermal Growth Factor Receptor (EGFR) is a transmembrane receptor tyrosine kinase of the ErbB family. Binding of the protein to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. Binding of EGFR can activate at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. [from Gene Cards, EGFR; 2016.09.30]
Many to one: 4 human to 1 Drosophila. The human genes are EGFR, ERBB4, ERBB2, and ERBB3.
Many to one: 4 human to 1 Drosophila. The human genes are EGFR, ERBB4, ERBB2, and ERBB3.
Many to one: 4 human to 1 Drosophila. The human genes are EGFR, ERBB4, ERBB2, and ERBB3.
Many to one: 4 human to 1 Drosophila. The human genes are EGFR, ERBB4, ERBB2, and ERBB3.
Moderate- to high-scoring ortholog of human EGFR, ERBB4, ERBB2, and ERBB3 (1 Drosophila to 4 human). Dmel\Egfr shares 33-37% identity and 46-51% similarity with the human genes.
Moderate-scoring ortholog of human RHBDL2, RHBDL1, and RHBDL3 (multiple Drosophila to multiple human). Dmel\ru shares 35% identity and 53% similarity with RHBDL2.
Low-scoring ortholog of several members of the epidermal growth factor (EGF) family of proteins in human.
