TY - JOUR
T1 - VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy
AU - Ramachandran, Nivetha
AU - Munteanu, Iulia
AU - Wang, Peixiang
AU - Ruggieri, Alessandra
AU - Rilstone, Jennifer J.
AU - Israelian, Nyrie
AU - Naranian, Taline
AU - Paroutis, Paul
AU - Guo, Ray
AU - Ren, Zhi Ping
AU - Nishino, Ichizo
AU - Chabrol, Brigitte
AU - Pellissier, Jean Francois
AU - Minetti, Carlo
AU - Udd, Bjarne
AU - Fardeau, Michel
AU - Tailor, Chetankumar S.
AU - Mahuran, Don J.
AU - Kissel, John T.
AU - Kalimo, Hannu
AU - Levy, Nicolas
AU - Manolson, Morris F.
AU - Ackerley, Cameron A.
AU - Minassian, Berge A.
N1 - Funding Information:
Acknowledgments 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 Franc¸aise 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.
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
KW - Autophagy
KW - Lysosomal acidification
KW - Splicing mutations
KW - Vacuolar ATP-ase
KW - Vacuolar myopathy
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U2 - 10.1007/s00401-012-1073-6
DO - 10.1007/s00401-012-1073-6
M3 - Article
C2 - 23315026
AN - SCOPUS:84876840432
SN - 0001-6322
VL - 125
SP - 439
EP - 457
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 3
ER -