Ramachandran, N and Munteanu, I and Wang, PX and Aubourg, P and Rilstone, JJ and Israelian, N and Naranian, T and Paroutis, P and Guo, R and Ren, ZP and Nishino, I and Chabrol, B and Pellissier, JF and Minetti, C and Udd, B and Fardeau, M and Tailor, CS and Mahuran, DJ and Kissel, JT and Kalimo, H and Levy, N and Manolson, MF and Ackerley, CA and Minassian, BA (2009) VMA21 Deficiency Causes an Autophagic Myopathy by Compromising V-ATPase Activity and Lysosomal Acidification (Retracted article. See vol. 142, pg. 984, 2010). CELL , 137 (2) 235 - 246. 10.1016/j.cell.2009.01.054.
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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 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.
|Title:||VMA21 Deficiency Causes an Autophagic Myopathy by Compromising V-ATPase Activity and Lysosomal Acidification (Retracted article. See vol. 142, pg. 984, 2010)|
|Keywords:||X-LINKED MYOPATHY, RENAL TUBULAR-ACIDOSIS, EXCESSIVE AUTOPHAGY, SKELETAL-MUSCLES, SUBUNIT, MUTATIONS, PROTEIN, MICE, CARDIOMYOPATHY, OSTEOPETROSIS|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > Department of Neurosciences and Mental Health > ICH - Dubowitz Neuromuscular Centre|
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