VMA21 Deficiency Causes an Autophagic Myopathy by Compromising V-ATPase Activity and Lysosomal Acidification

Nivetha Ramachandran, Iulia Munteanu, Peixiang Wang, Pauline Aubourg, 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

56 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 it is an essential assembly chaperone of the 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 upregulates the mTOR pathway and mTOR-dependent macroautophagy, resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge together, and vacuolate the cell. Our results uncover macroautophagic overcompensation leading to cell vacuolation and tissue atrophy as a mechanism of disease.

Original languageEnglish (US)
Pages (from-to)235-246
Number of pages12
Issue number2
StatePublished - Apr 17 2009



ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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