title: VMA21 deficiency causes an autophagic myopathy by compromising V-ATPase activity and lysosomal acidification.
abstract: 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.
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Nivetha
authors.initials: N
authors.lastname: Ramachandran
authors.forename: Iulia
authors.initials: I
authors.lastname: Munteanu
authors.forename: Peixiang
authors.initials: P
authors.lastname: Wang
authors.forename: Pauline
authors.initials: P
authors.lastname: Aubourg
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Rilstone
authors.forename: Nyrie
authors.initials: N
authors.lastname: Israelian
authors.forename: Taline
authors.initials: T
authors.lastname: Naranian
authors.forename: Paul
authors.initials: P
authors.lastname: Paroutis
authors.forename: Ray
authors.initials: R
authors.lastname: Guo
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Ren
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.forename: Brigitte
authors.initials: B
authors.lastname: Chabrol
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Pellissier
authors.forename: Carlo
authors.initials: C
authors.lastname: Minetti
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.forename: Michel
authors.initials: M
authors.lastname: Fardeau
authors.forename: Chetankumar S
authors.initials: CS
authors.lastname: Tailor
authors.forename: Don J
authors.initials: DJ
authors.lastname: Mahuran
authors.forename: John T
authors.initials: JT
authors.lastname: Kissel
authors.forename: Hannu
authors.initials: H
authors.lastname: Kalimo
authors.forename: Nicolas
authors.initials: N
authors.lastname: Levy
authors.forename: Morris F
authors.initials: MF
authors.lastname: Manolson
authors.forename: Cameron A
authors.initials: CA
authors.lastname: Ackerley
authors.forename: Berge A
authors.initials: BA
authors.lastname: Minassian
mesh_terms: D001343:Autophagy; D050172:Genes, X-Linked; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; C091909:VMA21 protein, S cerevisiae; C540401:VMA21 protein, human; D025262:Vacuolar Proton-Translocating ATPases