4.7 Article

Bi-allelic truncating mutations in VWA1 cause neuromyopathy

期刊

BRAIN
卷 144, 期 2, 页码 574-583

出版社

OXFORD UNIV PRESS
DOI: 10.1093/brain/awaa418

关键词

VWA1; mutations; neuromyopathy; exome sequencing

资金

  1. intramural for tune program [2554-0-0]
  2. German Bundesministerium fur Bildung und Forschung (BMBF) through the Juniorverbund in der Systemmedizin mitOmics [FKZ 01ZX1405C]
  3. intramural fortune program [2435-0-0]
  4. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [418081722]
  5. European Reference Network for Rare Neurological Diseases (ERN-RND) [739510]

向作者/读者索取更多资源

The VWA1 protein is a new disease gene associated with neuromuscular disorders, causing muscle weakness in patients with common early childhood foot deformities. The disease presents with neurogenic and myopathic pathology features.
The von Willebrand Factor A domain containing 1 protein, encoded by VWA1, is an extracellular matrix protein expressed in muscle and peripheral nerve. It interacts with collagen VI and perlecan, two proteins that are affected in hereditary neuromuscular disorders. Lack of VWA1 is known to compromise peripheral nerves in a Vwa1 knock-out mouse model. Exome sequencing led us to identify bi-allelic loss of function variants in VWA1 as the molecular cause underlying a so far genetically undefined neuromuscular disorder. We detected six different truncating variants in 15 affected individuals from six families of German, Arabic, and Roma descent. Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed. Our findings establish VWA1 as a new disease gene confidently implicated in this autosomal recessive neuromyopathic condition presenting with child-/adult-onset muscle weakness as a key clinical feature.

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