The missense mutation C667F in murine β-dystroglycan causes embryonic lethality, myopathy and blood-brain barrier destabilization

Abstract

Dystroglycan (DG) is an extracellular matrix receptor consisting of an α- and a β-DG subunit encoded by the DAG1 gene. The homozygous mutation (c.2006G>T, p.Cys669Phe) in β-DG causes Muscle-Eye-Brain disease with multicystic leukodystrophy in humans. In a mouse model of this primary dystroglycanopathy, approximately two-thirds of homozygous embryos fail to develop to term. Mutant mice that are born undergo a normal postnatal development but show a late-onset myopathy with partially penetrant histopathological changes and an impaired performance on an activity wheel. Their brains and eyes are structurally normal, but the localization of mutant β-DG is altered in the glial perivascular endfeet resulting in a perturbed protein composition of the blood-brain and blood-retina barrier. In addition, α- and β-DG protein levels are significantly reduced in muscle and brain of mutant mice. Due to the partially penetrant developmental phenotype of the C669F-β-DG mice, they represent a novel and highly valuable mouse model to study the molecular effects of β-DG functional alterations both during embryogenesis and in mature muscle, brain and eye, and to gain insight into the pathogenesis of primary dystroglycanopathies.

Translating multiscale research in rare disease

“…The DAG1 gene encodes two subunits, highly glycosylated α-dystroglycan (DG) and the transmembrane β-DG, which are primarily responsible for linking the cytoskeleton to the extracellular matrix. The study by Tan et al (2024) produced and characterised a mouse model harbouring a C667F variant in DAG1 , which was initially observed in a family with two affected individuals with muscle–eye–brain disease. Only one-third of the homozygous mice developed to birth and these mice developed a late-onset myopathy characterised by histology and muscle function.…”