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General Information
Name
cardiomyopathy, hypertrophic (postulated), EGFR/ERBB-related
FlyBase ID
FBhh0000756
OMIM
Overview

This report describes cardiomyopathy, hypertrophic (postulated), EGFR/ERBB-related. Work done in flies using the Dmel\Egfr gene implicates this gene family in the development of hypertrophic 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 and Hsap\ERBB3 genes have been introduced into flies, but have not been used in the context of this disease model.

A UAS-driven constitutively activated form of Dmel\Egfr, 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.

Amorphic mutations of Dmel\Egfr act as recessive embryonic lethals; they also act as cell lethals in somatic clones. Gain-of-function alleles exhibit dominant visible phenotypes. Extensive physical and genetic interactions have been described; see below and in the gene report for Egfr.

Loss-of-function and dominant-negative alleles of Dmel\Egfr have been used to model dilated cardiomyopathy in flies; see the human disease model 'cardiomyopathy, dilated (postulated), EGFR/ERBB-related' (FBhh0001001). 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.

One of the human orthologs of Dmel\Egfr, ERBB4, is implicated in amyotrophic lateral sclerosis 19 (OMIM:600543). Note that there is a another example of a connection between a fly model of cardiomyopathy and a gene implicated in amyotrophic lateral sclerosis: see FBhh0000705 and FBhh0000023 (ALS18).

[updated Oct. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: cardiomyopathy, familial hypertrophic
Symptoms and phenotype

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]

Specific Disease Summary: cardiomyopathy, hypertrophic (postulated), EGFR/ERBB-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype

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).

Genetics
Cellular phenotype and pathology
Molecular information

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]

External links
Disease synonyms
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 4 human to 1 Drosophila. The human genes are EGFR, ERBB4, ERBB2, and ERBB3.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 4 human to 1 Drosophila. The human genes are EGFR, ERBB4, ERBB2, and ERBB3.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 4 human to 1 Drosophila. The human genes are EGFR, ERBB4, ERBB2, and ERBB3.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 4 human to 1 Drosophila. The human genes are EGFR, ERBB4, ERBB2, and ERBB3.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Epidermal growth factor receptor (Egfr) encodes the transmembrane tyrosine kinase receptor for signaling ligands (encoded by grk, spi, vn, and Krn) in the TGFα family, which utilises the intracellular MAP kinase pathway. The product of Egfr contributes to growth regulation, cell survival and developmental patterning. [Date last reviewed: 2019-06-06]
    Gene Groups / Pathways
    Comments on ortholog(s)

    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.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (33 groups)
    RNA-protein
    Interacting group
    Assay
    References
    rna three hybrid
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, anti tag western blot, solid phase assay, tag visualisation by fluorescence
    anti bait coimmunoprecipitation, western blot
    anti bait coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, western blot, pull down, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
    anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, peptide massfingerprinting, pull down, two hybrid
    anti tag coimmunoprecipitation, western blot, pull down, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, western blot, enzyme linked immunosorbent assay, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot, pull down, western blot
    anti tag coimmunoprecipitation, anti tag western blot, pull down, western blot
    pull down, western blot, anti tag coimmunoprecipitation, anti tag western blot, two hybrid, anti bait coimmunoprecipitation
    anti bait coimmunoprecipitation, western blot
    surface plasmon resonance, solid phase assay, tag visualisation by fluorescence, x-ray crystallography
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot, two hybrid
    two hybrid, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, peptide massfingerprinting
    Alleles Reported to Model Human Disease (Disease Ontology) (10 alleles)
    Models Based on Experimental Evidence ( 2 )
    Modifiers Based on Experimental Evidence ( 8 )
    Models Based on Experimental Evidence ( 1 )
    Modifiers Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Interaction
    References
    Genetic Tools, Stocks and Reagents
    Sources of Stocks
    Contact lab of origin for a reagent not available from a public stock center.
    Bloomington Stock Center Disease Page
    Selected mammalian transgenes
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila transgenes
    Allele
    Transgene
    Publicly Available Stocks
    RNAi constructs available
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila classical alleles
    Allele
    Allele class
    Mutagen
    Publicly Available Stocks
    loss of function allele
    ethyl methanesulfonate
    loss of function allele
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    gamma ray
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    loss of function allele
    ethyl methanesulfonate
    loss of function allele
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    loss of function allele
    ethyl methanesulfonate
    loss of function allele
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    gamma ray
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    amorphic allele - genetic evidence
    gamma ray
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    References (4)