Vacuolar ATPase assembly integral membrane protein VMA21 (VMA21)

Vacuolar ATPase assembly integral membrane protein VMA21 (VMA21) is an evolutionarily conserved, small, integral endoplasmic reticulum (ER) membrane protein that acts as a specific chaperone essential for the assembly of the V0 sector of the vacuolar H+-ATPase (V-ATPase) complex. VMA21 ensures proper assembly and ER export of the V-ATPase complex to the lysosome, critical for lysosomal acidification and autophagy. Mutations in VMA21 cause X-linked myopathy with excessive autophagy (XMEA), manifesting as progressive, often childhood-onset, muscle weakness with autophagic vacuole accumulation in muscle fibers, and can also lead to liver dysfunction and congenital disorders of glycosylation. VMA21 deficiencies lead to defective degradation of phagocytosed and autophagic material, disturbed cholesterol and lipid metabolism, metabolic stress, and multi-organ dysfunction. Key evidence for its molecular and therapeutic relevance: - VMA21 variants disrupt V-ATPase assembly, lysosomal acidification, and lead to specific pathologies such as XMEA and CDG. - It is a therapeutic target in rare autophagic and metabolic diseases but is not a classical receptor or enzyme. - Drugs such as edaravone and LY294002 have shown beneficial effects in preclinical (zebrafish) models by partially restoring autophagic flux. - Due to its fundamental cellular role, systemic therapeutic targeting carries significant safety challenges.

Other names

Myopathy with excessive autophagy proteinMEAXXMEAVMA21 vacuolar H+-ATPase homologVacuolar ATPase assembly factorVacuolar ATPase assembly factor VMA21

Enhancement of autophagic flux through restoration of lysosomal acidification (for edaravone, LY294002; in experimental models)