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General Information
Name
muscular dystrophy, DAG1-related
FlyBase ID
FBhh0000192
Disease Ontology Term
Parent Disease
OMIM
Overview

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]

Disease Summary Information
Disease Summary: muscular dystrophy, DAG1-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype

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]

Genetics

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]

Cellular phenotype and pathology

The brain malformation cobblestone lissencephaly (type II lissencephaly) is observed in severe forms of α-dystroglycanopathy (Yamamoto, et al., 2014; pubmed:25403635).

Molecular information

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]

External links
Disease synonyms
α-dystroglycanopathies
muscular dystrophy-dystroglycanopathy (limb-girdle), type C9
limb-girdle muscular dystrophy-dystroglycanopathy, type C9
MDDGC9
LGMD2P
limb-girdle muscular dystrophy
limb-girdle muscular dystrophy-dystroglycanopathy
lissencephaly, DAG1-related
cobblestone lissencephaly
lissencephaly type II
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

One to one: 1 human to 1 Drosophila.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (5)
    Gene Snapshot
    Dystroglycan (Dg) encodes a major non-integrin extracellular matrix (ECM) receptor that connects the ECM to the actin cytoskeleton. It regulates animal survival and temperature preference, muscle integrity, myotendinous and neuromuscular junction formation and function, nervous system development, axon pathfinding, rhabdomere differentiation, neuronal stem cell division and epithelial polarity. [Date last reviewed: 2019-03-07]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Moderate-scoring ortholog of human DAG1 (1 Drosophila to 1 human). Dmel\Dg shares 23% identity and 36% similarity with the human gene.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Gene Snapshot
    In progress.Contributions welcome.
    Molecular function (GO)
      Cellular component (GO)
        Gene Groups / Pathways
        Comments on ortholog(s)

        Homologous to the human microRNA MIR92A (FBrf0242402).

        Orthologs and Alignments from DRSC
        DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
        Gene Snapshot
        In progress.Contributions welcome.
        Molecular function (GO)
          Cellular component (GO)
            Gene Groups / Pathways
            Comments on ortholog(s)

            Homologous to several human microRNAs, including MIR92A and MIR928 (FBrf0242402).

            Orthologs and Alignments from DRSC
            DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
            Gene Snapshot
            In progress.Contributions welcome.
            Molecular function (GO)
              Cellular component (GO)
                Gene Groups / Pathways
                Comments on ortholog(s)

                Homologous to several human microRNAs, including MIR92A and MIR25 (FBrf0242402).

                Orthologs and Alignments from DRSC
                DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
                Gene Snapshot
                In progress.Contributions welcome.
                Molecular function (GO)
                  Cellular component (GO)
                    Gene Groups / Pathways
                    Comments on ortholog(s)

                    Homologous to several human microRNAs, including MIR92A, MIR928 and MIR25 (FBrf0242402).

                    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 (47 groups)
                    protein-protein
                    Interacting group
                    Assay
                    References
                    anti tag coimmunoprecipitation, western blot
                    anti tag coimmunoprecipitation, western blot
                    fluorescence polarization spectroscopy, predetermined participant
                    anti tag coimmunoprecipitation, Identification by mass spectrometry, western blot
                    anti tag coimmunoprecipitation, western blot, Identification by mass spectrometry
                    anti tag coimmunoprecipitation, western blot
                    anti tag coimmunoprecipitation, Identification by mass spectrometry, western blot
                    anti bait coimmunoprecipitation, western blot
                    RNA-RNA
                    Interacting group
                    Assay
                    References
                    quantitative reverse transcription pcr, luminiscence technology, immunohistochemistry
                    luminiscence technology
                    luminiscence technology
                    luminiscence technology, quantitative reverse transcription pcr, immunohistochemistry
                    quantitative reverse transcription pcr, luminiscence technology, immunohistochemistry
                    luminiscence technology, immunohistochemistry, quantitative reverse transcription pcr
                    luminiscence technology, quantitative reverse transcription pcr, immunohistochemistry
                    RNA-RNA
                    Interacting group
                    Assay
                    References
                    western blot, luminiscence technology
                    quantitative reverse transcription pcr, luminiscence technology, immunohistochemistry
                    quantitative reverse transcription pcr, luminiscence technology
                    western blot, luminiscence technology, necessary binding region
                    luminiscence technology
                    quantitative reverse transcription pcr, luminiscence technology
                    fluorescence technology
                    luminiscence technology, quantitative reverse transcription pcr
                    RNA-RNA
                    Interacting group
                    Assay
                    References
                    western blot, luminiscence technology
                    luminiscence technology, quantitative reverse transcription pcr, immunohistochemistry
                    luminiscence technology, quantitative reverse transcription pcr
                    luminiscence technology
                    western blot, luminiscence technology, necessary binding region
                    luminiscence technology
                    quantitative reverse transcription pcr, luminiscence technology
                    fluorescence technology
                    quantitative reverse transcription pcr, luminiscence technology
                    RNA-RNA
                    Interacting group
                    Assay
                    References
                    luminiscence technology, western blot
                    luminiscence technology, quantitative reverse transcription pcr, immunohistochemistry
                    quantitative reverse transcription pcr, luminiscence technology
                    western blot, luminiscence technology, necessary binding region
                    luminiscence technology
                    quantitative reverse transcription pcr, luminiscence technology
                    quantitative reverse transcription pcr, luminiscence technology
                    RNA-RNA
                    Interacting group
                    Assay
                    References
                    luminiscence technology, western blot
                    fluorescence technology
                    luminiscence technology, immunohistochemistry, quantitative reverse transcription pcr
                    fluorescence technology
                    luminiscence technology, quantitative reverse transcription pcr
                    luminiscence technology, necessary binding region, western blot
                    luminiscence technology
                    luminiscence technology, quantitative reverse transcription pcr
                    fluorescence technology
                    luminiscence technology, quantitative reverse transcription pcr
                    RNA-protein
                    Interacting group
                    Assay
                    References
                    enzymatic study, autoradiography
                    Alleles Reported to Model Human Disease (Disease Ontology) (10 alleles)
                    Models Based on Experimental Evidence ( 5 )
                    Modifiers Based on Experimental Evidence ( 3 )
                    Allele
                    Disease
                    Interaction
                    References
                    Models Based on Experimental Evidence ( 1 )
                    Modifiers Based on Experimental Evidence ( 0 )
                    Allele
                    Disease
                    Interaction
                    References
                    Models Based on Experimental Evidence ( 2 )
                    Modifiers Based on Experimental Evidence ( 0 )
                    Allele
                    Disease
                    Interaction
                    References
                    Models Based on Experimental Evidence ( 1 )
                    Allele
                    Disease
                    Evidence
                    References
                    Modifiers Based on Experimental Evidence ( 0 )
                    Allele
                    Disease
                    Interaction
                    References
                    Models Based on Experimental Evidence ( 1 )
                    Modifiers Based on Experimental Evidence ( 0 )
                    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
                    Delta2-3 transposase
                    ethyl methanesulfonate
                    References (15)