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General Information
Name
dilated cardiomyopathy 1NN
FlyBase ID
FBhh0000156
Disease Ontology Term
Parent Disease
Overview

This report describes dilated cardiomyopathy 1NN (CMD1NN), which is a subtype of dilated cardiomyopathy; CMD1NN exhibits an autosomal dominant pattern of inheritance. The human gene implicated in this disease is RAF1, which encodes the Raf-1 proto-oncogene, serine/threonine kinase. RAF1 is also associated with the diseases LEOPARD syndrome 2 (OMIM:611554, FBhh0000132) and Noonan syndrome 5 (OMIM:611553, FBhh0000131).

This specific disease has not been modeled in flies. For information about a disease model for cardiomyopathy related to RAF, see the human disease model report 'cardiomyopathy, hypertrophic (postulated), RAF-related' (FBhh0000737).

A UAS construct for the human Hsap\RAF1 gene has been introduced into flies, but has not been characterized in the context of this disease model (see FBhh0000737).

[updated Jul. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: dilated cardiomyopathy
Symptoms and phenotype

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 OMIM:115200, 2016.01.27]

Specific Disease Summary: dilated cardiomyopathy 1NN
OMIM report

[CARDIOMYOPATHY, DILATED, 1NN; CMD1NN](https://omim.org/entry/615916)

Human gene(s) implicated

[RAF1 PROTOONCOGENE, SERINE/THREONINE KINASE ; RAF1](https://omim.org/entry/164760)

Symptoms and phenotype

Of 10 patients in whom age of onset was known, 8 presented in childhood or adolescence. The average age at presentation was 12.6 years, which the authors noted was younger than the approximate average of 20 years associated with CMD caused by sarcomeric gene mutations (Dhandapany et al., 2014, pubmed:24777450). [From OMIM:615916, 2016.01.28]

Genetics

Dilated cardiomyopathy-1NN (CMD1NN) is caused by heterozygous mutation in the RAF1 gene. [From OMIM:615916 2016.01.28]

Cellular phenotype and pathology
Molecular information

RAF1 is a serine-threonine kinase that activates MEK1 (OMIM:176872) and MEK2 (OMIM:601263). Ectopically expressed RAF1 mutants from the two hypertrophic cardiomyopathy (CMH; see OMIM:192600) hotspots (around ser259 or ser612) linked to LEOPARD syndrome 2 and/or Noonan syndrome 5 had increased kinase activity and enhanced ERK (see 176948) activation, whereas non-CMH-associated mutants were kinase impaired. (Pandit et al., 2007, pubmed:17603483). Mutations in the CR2 domain, but not the CR3 domain, of RAF1 are associated with hypertrophic cardiomyopathy (Razzaque et al., 2007, pubmed:17603482). [From OMIM:611553 and OMIM:164760, 2016.01.19]

External links
Disease synonyms
CMD1NN
cardiomyopathy, dilated, 1NN; CMD1NN
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 3 human to 1 Drosophila.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (0)
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (0 groups)
    Alleles Reported to Model Human Disease (Disease Ontology) (1 alleles)
    Models Based on Experimental Evidence ( 1 )
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    Modifiers Based on Experimental Evidence ( 1 )
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    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
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    Selected Drosophila transgenes
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    RNAi constructs available
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    Selected Drosophila classical alleles
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    Publicly Available Stocks
    References (3)