VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy

Nivetha Ramachandran, Iulia Munteanu, Peixiang Wang, Alessandra Ruggieri, Jennifer J. Rilstone, Nyrie Israelian, Taline Naranian, Paul Paroutis, Ray Guo, Zhi Ping Ren, Ichizo Nishino, Brigitte Chabrol, Jean Francois Pellissier, Carlo Minetti, Bjarne Udd, Michel Fardeau, Chetankumar S. Tailor, Don J. Mahuran, John T. Kissel, Hannu KalimoNicolas Levy, Morris F. Manolson, Cameron A. Ackerley, Berge A. Minassian

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


X-linked Myopathy with Excessive Autophagy (XMEA) is a childhood onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p, VMA21 is an essential assembly chaperone of the vacuolar ATPase (V-ATPase), the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids which leads to downregulation of the mTORC1 pathway, and consequent increased macroautophagy resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge, and vacuolate the cell. Our results uncover a novel mechanism of disease, namely macroautophagic overcompensation leading to cell vacuolation and tissue atrophy.

Original languageEnglish (US)
Pages (from-to)439-457
Number of pages19
JournalActa Neuropathologica
Issue number3
StatePublished - Mar 2013


  • Autophagy
  • Lysosomal acidification
  • Splicing mutations
  • Vacuolar ATP-ase
  • Vacuolar myopathy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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