Absence of α- and β-dystroglycan is associated with Walker-Warburg syndrome

Abstract

A loss-of-function mutation in DAG1 can result in Walker-Warburg syndrome and is not embryonic lethal.

Neuromuscular junction immaturity and muscle atrophy are hallmarks of the ColQ‐deficient mouse, a model of congenital myasthenic syndrome with acetylcholinesterase deficiency

“…Hypomorphic mutations in perlecan are responsible for Schwartz‐Jampel Syndrome (SJS), which is also characterized by very low levels of AChE in patients (10, 12). DG loss‐of‐function mutations lead to Walker‐Warburg syndrome, the most severe variant of the muscular dystrophy‐dystroglycanopathy syndromes (18), and AChE is absent from NMJs of DG‐null mice (9). However, despite this common defect in AChE, patients with CMS with AChE deficiency, SJS, and DG deficiency exhibit a clearly different phenotype.…”

220th ENMC workshop: Dystroglycan and the dystroglycanopathies Naarden, The Netherlands, 27–29 May 2016

“…Indeed, Western blot analysis and laminin-overlay analysis confirmed the absence of both dystroglycan subunits in patient myoblasts. This is the first report of a full DAG1 loss-of-function allele in humans ( [2]). The associated phenotype is severe and associated with early lethality.…”

A molecular overview of the primary dystroglycanopathies

“…25 A complete lack of DG has also been observed in another zebrafish mutant in which a nonsense mutation was found within the mucin-like region of α-DG. 10 Our group has a long-standing tradition of molecular studies on DG, for example by modelling and molecular dynamics, we have shown that the V567D zebrafish mutation, as well as its murine topological counterpart I591D, is likely to introduce a degree of instability/ collapse within the α-DG IG-like β-sandwich structure, leading to the exposure of some hydrophobic internal residues. 10 Our group has a long-standing tradition of molecular studies on DG, for example by modelling and molecular dynamics, we have shown that the V567D zebrafish mutation, as well as its murine topological counterpart I591D, is likely to introduce a degree of instability/ collapse within the α-DG IG-like β-sandwich structure, leading to the exposure of some hydrophobic internal residues.…”

“…24 It is worth to note that the case identified by Riemersma and colleagues (with a nonsense stop codon at the level of the S6 domain of α-DG resulting in the full depletion of the whole DG complex) might represent the nearest human counterpart to these mutations. 10 Our group has a long-standing tradition of molecular studies on DG, for example by modelling and molecular dynamics, we have shown that the V567D zebrafish mutation, as well as its murine topological counterpart I591D, is likely to introduce a degree of instability/ collapse within the α-DG IG-like β-sandwich structure, leading to the exposure of some hydrophobic internal residues. 34 In another case, the C669F mutation affecting the ectodomain of β-DG was shown to cause a severe Muscle-Eye-Brain disease with a relevant phenotype involving the white matter in the brain displaying as multicystic leukodystrophy.…”