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FLASH GENE
Symbol DAG1 contributors: mct/shn - updated : 12/01/2015
HGNC name dystroglycan 1 (dystrophin-associated glycoprotein 1)
HGNC id 2666
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • dystroglycan-type cadherin-like domain
  • one peptidase S72 domain
    • conjugated GlycoP
    isoforms Precursor T precursor of the 43kDa DYS associated transmembrane glycoprotein DAG beta (dystroglycan beta)
    HOMOLOGY
    interspecies ortholog to DAG1, pan troglodytes
    ortholog to Dag1, Mus musculus
    ortholog to Dag1, Rattus norvegicus
    ortholog to dag1, danio rerio
    Homologene
    FAMILY
    CATEGORY receptor
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,cytoskeleton
    text
  • alpha DG is secreted whereas beta-DG is localized at the cytoskeleton
  • localized at costameres and neuromuscular junctions in the sarcolemma of skeletal muscle (Ayalon 2008)
    • basic FUNCTION
  • required for the development of Reichert's membrane
  • required for the formation of a basement membrane in embryoid bodies
  • necessary for myofibre survival and synapse differentiation or stability
  • acting as a Schwann cell receptor for mycobacterium leprae, in the presence of the G domain of LAMA2
  • major organizer of extracellular matrix proteins, of the neuromuscular function and of synaptic components
  • playing a role in the regulation of the actin cytoskeleton, transduction of signals from the extracellular matrix to the cytoskeleton and regulation of the cell morphology
  • a key signaling component in the Notch pathway
  • necessary for Laminin enhancement of filopodial formation, process outgrowth, and process branching in differentiating oligodendroglia
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • a 156kDa extracellular component DAG alpha (dystroglycan alpha) membrane associated through a non covalent interaction with the extracellular domain of DAG beta
  • bound to laminin 2 (alpha 2,beta 1,gamma 1) and to agrin and perlecan, multifunctional protein critical in the formation of extracellular matrix in cells contacting basement membranes
  • connecting the intracellular cytoskeleton to ECM and protecting muscle from mechanical injury
  • receptor for lymphocytic choriomeningitis virus and Lassa fever virus
    • INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • ions Ca2+ binding
    • protein
  • agrin
  • laminin A/B1/B2 and merosin M/B1/B2
  • laminin-1
  • dystrophin
  • Biglycan
  • utrophin
  • growth factor receptor 2, Grb2
  • Caveolin-3
  • rapsyn RING-H2 domain
  • AGR2 and AGR3
  • AGR
  • DAG1 function requires xylosyl- and glucuronyltransferase activities of LARGE to bind laminin-G domain-containing ECM ligands
  • CHST10 suppressed the glycosylation and reduced the ligand binding activity of DAG1
  • sulfate transfer induced by CHST10 plays a regulatory role in the formation of functional glycans DAG1
  • GYLTL1B regulates functional DAG1 glycosylation in prostate cancer cell lines
  • POMGNT2 might encode O-GlcNAc transferase that specifically glycosylates DAG1
  • interacts with DAG1 and controls motility and mechanical properties of Schwann cells
  • POMGNT1 stem region modulates O-mannosylation sites of DAG1, by its carbohydrate-binding domain
  • TRAPPC11 and another membrane trafficking protein, GOSR2, implicated in DAG1 hypoglycosylation
    • cell & other
    REGULATION
    activated by activated MUSK binding dystroglycan is regulated by alternative mRNA splicing of agrin
    Other precursor of the 43kDa DYS associated transmembrane glycoprotein DAG beta (dystroglycan beta)
    O-mannosyl phosphorylation is required for laminin binding, and when defective, may have a role in congenital muscular dystrophy (Yoshida-Moriguchi 2010)
    ASSOCIATED DISORDERS
    corresponding disease(s) SCARMD4 , DEL3P21
    Susceptibility
    Variant & Polymorphism
    Candidate gene
  • defect of dystroglycan glycosylation may be a factor in cancer progression (de Bernabé 2009)
  • candidate gene for the site of mutation in autosomal recessive muscular dystrophies
    • Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Heterozygous Dag1neo2 mice are viable and fertile but homozygous Dag1neo2 embryos exhibit gross developmental abnormalities beginning around 6.5 days of gestation that is due to a disruption of Reichert's membrane
  • chimaeric mice generated with ES cells targeted for both dystroglycan alleles have skeletal muscles essentially devoid of dystroglycans and develop a progressive muscle pathology with many disrupted neuromuscular junctions
  • brain-selective deletion of dystroglycan in mice is sufficient to cause congenital muscular dystrophie-like brain malformations, including disarray of cerebral cortical layering, fusion of cerebral hemispheres and cerebellar folia, and aberrant migration of granule cells
  • striated muscle-specific disruption of the mouse Dag1 gene results in loss of the dystrophin-glycoprotein complex in differentiated muscle and a remarkably mild muscular dystrophy with hypertrophy and without tissue fibrosis
  • mouse harboring the Dag1 Thr192Met mutation display muscular dystrophy and cognitive impairment
  • Dg morpholino knockdown leads to disruption of epidermal differentiation by affecting the intercalation of multiciliated cells, deposition of laminin, and organization of fibronectin in the extracellular matrix
  • disruption of dystroglycan-Laminin interactions result in decreased filopodial number and length, decreased process length, and decreased numbers of primary and secondary processes