VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy
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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.
KeywordsVacuolar myopathy Autophagy Vacuolar ATP-ase Splicing mutations Lysosomal acidification
We wish to thank all the XMEA families. We are grateful to Drs. G. Israelian, V.C. Juel, M. Villanova, the late G. Karpati, S. Carpenter, and D. Figarella-Branger for the clinicopathologic diagnosis of some of the patients included in this study, previously published in clinical journals. We thank Drs. S. Grinstein for helpful discussions and Drs. J Rommens and S Meyn for their review of our manuscript, T. Sarkisyan, J. Kere, E. Heon, F. Zara and H. Lohi for ethnic control DNA samples, A. Leung for assistance with experiments in Supplemental Fig. 12, N. Ochtony for Supplemental Fig. 1A, P. Bradhsaw for assistance in deconvolution microscopy. Principal funding was from the Canadian Institutes of Health Research. The Association Française contre les Myopathies provided support to N. Levy, EVO Funds of Helsinki and Turku University Hospitals (Finland) and sports research grant from Ministry of Education of Finland to H. Kalimo, and the Natural Sciences and Engineering Research Council (Canada) to I. Munteanu.
Conflict of interest
The authors declare that they have no conflicts of interests.
This study was approved by the Research Ethics Board of the Hospital for Sick Children Toronto and informed consent was obtained from all subjects.