This report includes information relevant to a potential model of dilated cardiomyopathy 3B (CMD3B), which is a subtype of dilated cardiomyopathy. The gene implicated in this disease is dystrophin (DMD); there is a single orthologous gene in Drosophila, Dys. This subtype of dilated cardiomyopathy is one of several cases in which the implicated gene is also associated with muscular dystrophy (MD). In addition, dilated cardiomyopathy is frequently one of the symptoms of MD.
Muscular dystrophy is a genetically heterogenous disease with many implicated genes; the same gene may be associated with different levels of severity of disease or different subsets of muscles affected. See the human disease model report 'muscular dystrophy, dystrophin-related' (FBhh0000191). Both the human DMD gene and the fly Dys gene produce many alternative transcripts, primarily by variable use of multiple promoters, which results in isoforms with differing amino-terminal sequences, differing numbers of spectrin repeats, and common carboxy-terminal sequences. In flies, the role of different isoforms has been investigated using isoform-specific RNAi reagents.
Although the human DMD gene has not been introduced into flies, a UAS construct of the mouse gene, Mmus\Dmd, has been. The mouse DMD isoform used is one of the short forms (Dp116). Partial heterologous rescue (functional complementation) is observed: expression of the Mmus\Dmd gene in the fly heart ameliorates the the dilated cardiomyopathy phenotype observed for a loss-of-function genotype.
Using small deletions within the Dmel\Dys genomic region, a genotype with expression of only the shortest Dys isoform intact was created. These animals exhibit reduced lifespan and progressive heart phenotypes analogous to dilated cardiomyopathy. Physical interactions of the Dys protein product have been described; see below and in the gene report for Dys.
[updated Feb. 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]
[CARDIOMYOPATHY, DILATED, 3B; CMD3B](https://omim.org/entry/302045)
[DYSTROPHIN; DMD](https://omim.org/entry/300377)
See general description, above.
Dilated cardiomyopathy 3B is caused by mutation in the gene encoding dystrophin (DMD). [from MIM:302045; 2016.03.11]
Many to one: 3 human to 1 Drosophila; there are two lower-scoring orthologs in human, UTRN and DRP2.
Dmel\Dys is a high-scoring ortholog of the human gene DMD; it is a moderate-scoring ortholog of human genes UTRN and DRP2 (1 Drosophila to 3 human). Dmel\Dys shares 29% identity and 47% similarity with DMD and UTRN; these 3 proteins are of similar length and align along their whole lengths. DRP2 is a much shorter protein that aligns to the carboxy end of Dmel\Dys, DMD, and UTRN.
