DAG1 gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: dystroglycan 1
  • Glycosylation of alpha-dystroglycans helps anchor cytoskeleton to the lattice of proteins and other molecules in the extracellular matrix
  • Stabilise and protect muscle fibres
  • It also regulates many cellular processes that are important for cell stability, survival, orientation (polarity) and neuronal migration (particularly during early brain development)
Clinical phenotype
(OMIM phenotype no.)
  • Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9 (#616538)
  • Also known as Walker-Warburg syndrome (WWS)/Muscle Eye Brain Disease (MEB)
  • Muscular dystrophy-dystroglycanopathy (limb girdle), type C, 9 (#613818)
  • Defects in the glycosylation of alpha-dystroglycans cause 3 overlapping syndromes/dystroglycanopathies: WWS, MEB and Fukuyama type Congenital Muscular Dystrophy (FCMD; #253800)
  • WWS—most severe phenotype; MEB—intermediate phenotype; FCMD—mildest phenotype
  • Phenotype severity is determined by the extent which the mutation affects DAG1 glycosylation
Inheritance
  • Autosomal recessive
Ocular features
Systemic features
  • Congenital muscular dystrophy
  • Brain anomalies (cobblestone lissencephaly, hydrocephalus, hypoplastic cerebellar vermis, macrocephaly, microcephaly or anencephaly)
  • Severe hypotonia
  • Occasional seizures
  • Intellectual disability
  • Developmental delays
  • Patients with WWS have a severely limited lifespan with significant CNS and ocular anomalies
Key investigations
  • B-scan USS to measure axial length to document microphthalmia
  • Electrophysiology to determine visual potential
  • Measurement of intraocular pressure
  • Gonioscopy (if tolerated/EUA) or anterior segment OCT to identify angle abnormalities and any associated anterior segment dysgenesis
  • MRI brain and orbit
  • Systemic assessment with a paediatrician and other relevant specialists
  • Bloods (elevated creatinine kinase)
  • Skeletal muscle biopsy
Molecular diagnosisNext generation sequencing
  • Targeted gene panels
  • Whole genome sequencing
ManagementOcularSystemic
  • Multidisciplinary approach
Therapies under research
  • None at present
Further information

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References

  1.  Leibovitz Z, Mandel H, Falik-Zaccai TC, et al. Walker-Warburg syndrome and tectocerebellar dysraphia: A novel association caused by a homozygous DAG1 mutation. Eur J Paediatr Neurol 2018; 22: 525–531
  2.  Riemersma M, Mandel H, van Beusekom E, et al. Absence of α- and β-dystroglycan is associated with Walker-Warburg syndrome. Neurology 2015; 84: 2177–2182
  3.  Geis T, Marquard K, Rödl T, et al. Homozygous dystroglycan mutation associated with a novel muscle-eye-brain disease-like phenotype with multicystic leucodystrophy. Neurogenetics 2013; 14: 205–213
  4.  Francisco R, Pascoal C, Marques-da-Silva D, et al. Keeping an eye on congenital disorders of O-glycosylation: A systematic literature review. J Inherit Metab Dis. 2019;42(1):29-48

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Updated on November 30, 2020
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