In humans, multiple genes have been implicated in muscular dystrophy; in addition, in most cases, any specific gene is implicated in multiple forms of the disease. This report describes fly models of muscular dystrophy related to the gene dystrophin (DMD), which encodes multiple isoforms of a large protein associated with muscles. Dystrophin is part of the dystrophin-glycoprotein complex that bridges the inner muscle cytoskeleton and the extracellular matrix. The dystrophin gene is implicated in Duchenne type MD (FBhh0000210) and Becker type MD (FBhh0000211). Dystrophinopathies also include DMD-associated dilated cardiomyopathy (DCM) in which the heart is primarily affected; see dilated cardiomyopathy 3B (FBhh0000212). There is a high-scoring fly ortholog of DMD, Dmel\Dys, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Dys is a moderate-scoring ortholog of two additional human genes, UTRN and DRP2.
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. (See the human disease model report 'dilated cardiomyopathy 3B' FBhh0000212).
Animals homozygous for most loss-of-function alleles of Dmel\Dys are viable and fertile; they exhibit a mild, but fully penetrant, wing defect. RNAi-effected loss-of-function genotypes result in defects in the indirect flight muscles of the adult, progressive decline locomotor ability, and impaired response to severe hypoxia exposure. Phenotypic assays using the amorphic wing phenotype have allowed characterization of genetic interactions. An overlapping deletion genotype results in reduced lifespan and progressive heart phenotypes analogous to dilated cardiomyopathy (see FBhh0000212). The role of dystrophin in retinal health has also been investigated in flies. Physical interactions of the Dys protein product have been described; see below and in the gene report for Dys.
[updated Mar. 2021 by FlyBase; FBrf0222196]
Both the severe Duchenne muscular dystrophy (DMD; MIM:310200) and the milder Becker muscular dystrophy (BMD; MIM:300376) are the result of mutations in the extremely large gene that encodes dystrophin. [from MIM:310200; 2016.03.11]
Dystrophin mRNA is differentially spliced, producing a range of different transcripts, encoding a large set of protein isoforms. A representative gene product (Dp427) is a large, rod-like cytoskeletal protein which is found at the inner surface of muscle fibers. Dystrophin is part of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton (F-actin) and the extra-cellular matrix. [from Gene Cards, DMD; 2016.03.24]
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.
