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VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy

Nivetha Ramachandran1, Iulia Munteanu, Peixiang Wang

  • 1Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.

Acta Neuropathologica
|January 15, 2013
PubMed

Insights

X-linked Myopathy with Excessive Autophagy (XMEA) is caused by a faulty VMA21 gene, leading to impaired cellular waste removal. This results in muscle vacuolation and atrophy due to overactive autophagy.

Area of Science:

  • Cell Biology
  • Genetics
  • Neuromuscular Disorders

Background:

  • X-linked Myopathy with Excessive Autophagy (XMEA) is a childhood-onset skeletal muscle disease.
  • The pathogenesis of XMEA, characterized by muscle vacuolation and atrophy, remains incompletely understood.

Purpose of the Study:

  • To identify the genetic cause of XMEA.
  • To elucidate the molecular mechanism underlying XMEA pathogenesis.

Main Methods:

  • Genetic analysis of affected individuals.
  • Functional studies of the VMA21 gene and its protein product.
  • Investigation of lysosomal and autophagic pathways in patient-derived cells.

Main Results:

  • XMEA is caused by hypomorphic alleles of the VMA21 gene.
  • VMA21 is an essential assembly chaperone for the vacuolar ATPase (V-ATPase).
  • Reduced VMA21 function leads to increased lysosomal pH, impaired autophagy, and subsequent macroautophagic overcompensation, causing cellular vacuolation and atrophy.

Conclusions:

  • VMA21 dysfunction is the cause of XMEA.
  • Macroautophagic overcompensation represents a novel disease mechanism leading to skeletal muscle vacuolation and atrophy.

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