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 dystroglycan 1, also known as dystrophin-associated glycoprotein (DAG1); the dystrophin-glycoprotein complex links the extracellular matrix and the cytoskeleton in the skeletal muscle. The DAG1 gene is implicated in several forms of muscular dystrophy, see OMIM:128239 (see also FBhh0000207, FBhh0000208). There is a single fly ortholog, Dmel\Dg, for which classical hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
A UAS construct of the wild-type human Hsap\DAG1 gene has been introduced into flies; heterologous rescue has not been tested.
The more severe hypomorphic alleles of Dmel\Dg, when homozygous, are lethal in late larval stage; larval muscle phenotypes have been described. Precise levels of Dg appear to be critical: lower levels slow down neuronal stem cell division, while higher levels accelerate proliferation and perturb neuron differentiation. Animals with altered Dg levels, either loss- and gain-of-function mutants, exhibit a cobblestone brain phenotype (a type of lissencephaly). Adult phenotypes have allowed characterization of genetic interactions. Physical interactions of the Dg protein product have been described; see below and in the FlyBase gene report for Dg.
MicroRNAs of the mir-310 cluster (mir-310, mir-311, mir-312 and mir-313) bind to the extended 3'UTR of longer Dmel\Dg transcripts. Animals carrying a small deletion that removes all 4 genes of the mir-310 cluster exhibit a cobblestone brain phenotype.
[updated May 2019 by FlyBase; FBrf0222196]
Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. Muscle weakness typically presents from birth to early infancy. Affected infants typically appear "floppy" with low muscle tone and poor spontaneous movements. Affected children may present with delay or arrest of gross motor development together with joint and/or spinal rigidity. [Gene Reviews, Congenital Muscular Dystrophy Overview; 2019.05.31]
A form of limb-girdle muscular dystrophy-dystroglycanopathy (type C9; MDDGC9) is caused by homozygous mutation in the gene encoding alpha-dystroglycan (DAG1). A second more severe type of muscular dystrophy (OMIM:616538) is also associated with mutations in the DAG1 gene. [from OMIM:613818, OMIM:128239; 2016.03.11]
Dystroglycan is a central component of the dystrophin-glycoprotein complex that links the extracellular matrix and the cytoskeleton in the skeletal muscle. [from Gene Cards, DAG1, 2016.03.25]