Mutations in the V‐ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease

Abstract

BaCKgRoUND aND aIMS: Vacuolar H+-ATP complex (V-ATPase) is a multisubunit protein complex required for acidification of intracellular compartments. At least five different factors are known to be essential for its assembly in the endoplasmic reticulum (ER). Genetic defects in four of these V-ATPase assembly factors show overlapping clinical features, including steatotic liver disease and mild hypercholesterolemia. An exception is the assembly factor vacuolar ATPase assembly integral membrane protein (VMA21), whose X-linked mutations lead to autophagic myopathy. appRoaCH aND ReSUltS: Here, we report pathogenic variants in VMA21 in male patients with abnormal protein glycosylation that result in mild cholestasis, chronic elevation of aminotransferases, elevation of (low-density lipoprotein) cholesterol and steatosis in hepatocytes. We also show that the VMA21 variants lead to V-ATPase misassembly and dysfunction. As a consequence, lysosomal acidification and degradation of phagocytosed materials are impaired, causing lipid droplet (LD) accumulation in autolysosomes. Moreover, VMA21 deficiency triggers ER stress and sequestration of unesterified cholesterol in lysosomes, thereby activating the sterol response element-binding protein-mediated cholesterol synthesis pathways. CoNClUSIoNS: Together, our data suggest that impaired lipophagy, ER stress, and increased cholesterol synthesis lead to LD accumulation and hepatic steatosis. V-ATPase assembly defects are thus a form of hereditary liver disease with implications for the pathogenesis of nonalcoholic fatty liver disease.

Sugary Logistics Gone Wrong: Membrane Trafficking and Congenital Disorders of Glycosylation

“…This observation corresponds to the mislocalization of especially trans-Golgi-resident galactosyltransferases, which is consistent with the concomitant acidification of the Golgi apparatus. In contrast to VMA21-CDG [97], but in line with ATP6V0A2-CDG [48], no disorders in autophagy were described for TMEM199-CDG and CCDC115-CDG [101,102]. One explanation is that a potential lysosomal defect was not investigated.…”

“…Similarly, recently, a novel CDG involving the putative V-ATPase assembly factor VMA21 (ortholog of yeast Vma21p) was discovered, with patients presenting with a hepatic phenotype with steatosis and hypercholesterolemia [97]. Two mutations causing a premature stop codon and one missense mutation in VMA21 were discovered.…”

“…Two mutations causing a premature stop codon and one missense mutation in VMA21 were discovered. Mechanistically, the symptoms of VMA21-CDG patients are the result of impaired lipophagy due to reduced lysosomal acidification, and patients present with a loss of sialic acid and galactose on glycoproteins [97]. In yeast, Vma21p interacts with V 0 subunit c' and thus promotes the assembly of the V 0 proteolipid subunits into a ring ( Figure 2) [79,80].…”

Dissecting Total Plasma and Protein-Specific Glycosylation Profiles in Congenital Disorders of Glycosylation

“…The VMA21 genetic variant in P18 with an XMEA myopathy phenotype did not result in abnormal CDG screening via Tf glycosylation profiles [ 25 ]. However, the level of (antenna) fucosylation within A3 and A4 structures found in TPNG was higher for P18 as compared to the healthy controls, regardless of sialylation (A3F; 50.4% and A4F; 60.9%, control ranges: 16.0–38.3% and 27.3–49.7%, respectively; Supplementary Figure S2B ).…”

“…The diagnosis of all CDG patients was genetically and biochemically confirmed in previous studies [ 13 ]. P18 has X-linked myopathy with excessive autophagy (XMEA) due to mutations in VMA21 without abnormal CDG screening results [ 25 ].…”