title: Cardiac autophagic vacuolation in severe X-linked myopathy with excessive autophagy.
abstract: X-linked myopathy with excessive autophagy (XMEA), caused by mutations of the VMA21 gene, is a strictly skeletal muscle disease. Extensive studies in yeast established VMA21 as the master assembly chaperone of V-ATPase, the complex multisubunit proton pump that acidifies organelles and that is vital to all mammalian tissues. As such, skeletal muscle disease exclusivity in XMEA is highly surprising. We now show that the severest VMA21 mutation, c.164-6t>g, does result in XMEA-typical pathology with autophagic vacuolar changes outside skeletal muscle, namely in the heart. However, even patients with this mutation do not exhibit clinical extramuscular disease, including cardiac disease, despite extreme skeletal muscle wasting to the extent of ventilation dependence. Uncovering the unique skeletal muscle vulnerability to defective organellar acidification, and resultant tissue-destructive excessive autophagy, will be informative to the understanding of muscle physiology. Alternatively, understanding extramuscular resistance to VMA21 mutation might disclose heretofore unknown mammalian V-ATPase assembly chaperones other than VMA21.
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Iulia
authors.initials: I
authors.lastname: Munteanu
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Hannu
authors.initials: H
authors.lastname: Kalimo
authors.affiliation: Heart Center, Turku University Hospital and University of Turku, FI-20520 Turku, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Saraste
authors.affiliation: Dept. of Neuromuscular Research, National Centre of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada. Electronic address: berge.minassian@sickkids.ca.
authors.forename: Berge A
authors.initials: BA
authors.lastname: Minassian
mesh_terms: D001343:Autophagy; D002675:Child, Preschool; D017809:Fatal Outcome; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008297:Male; D009135:Muscular Diseases / Q000235:genetics / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics*; D014617:Vacuoles / Q000473:pathology*
chemical_list: C540401:VMA21 protein, human; D025262:Vacuolar Proton-Translocating ATPases
keywords: Acidification; Autophagy; CAVM; Congenital; LAMP2; Lysosome; XMEA