X-linked myopathy with excessive autophagy (XMEA) is a rare neuromuscular disorder caused by mutations in the gene, encoding a chaperone protein present in the endoplasmic reticulum (ER). In yeast and human, VMA21 has been shown to chaperone the assembly of the vacuolar (v)-ATPase proton pump required for the acidification of lysosomes and other organelles. In line with this, VMA21 deficiency in XMEA impairs autophagic degradation steps, which would be key in XMEA pathogenesis. Recent years have witnessed a surge of interest in , with the identification of novel mutations causing a congenital disorder of glycosylation (CDG) with liver affection, and its potent implication in cancer predisposition. With this, VMA21 deficiency has been further linked to defective glycosylation, lipid metabolism dysregulation and ER stress. Moreover, the identification of two VMA21 isoforms, namely VMA21-101 and VMA21-120, has opened novel avenues regarding the pathomechanisms leading to XMEA and -CDG. In this review, we discuss recent advances on the clinical spectrum associated with VMA21 deficiency and on the pathophysiological roles of VMA21.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1177/22143602251314767 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Recent advances in the clinical spectrum and pathomechanisms associated with X-linked myopathy with excessive autophagy and other -related disorders.
J Neuromuscul Dis
March 2025
Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
X-linked myopathy with excessive autophagy (XMEA) is a rare neuromuscular disorder caused by mutations in the gene, encoding a chaperone protein present in the endoplasmic reticulum (ER). In yeast and human, VMA21 has been shown to chaperone the assembly of the vacuolar (v)-ATPase proton pump required for the acidification of lysosomes and other organelles. In line with this, VMA21 deficiency in XMEA impairs autophagic degradation steps, which would be key in XMEA pathogenesis.
View Article and Find Full Text PDFIdentification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis.
Hum Mol Genet
December 2023
Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva, Switzerland.
Defective lysosomal acidification is responsible for a large range of multi-systemic disorders associated with impaired autophagy. Diseases caused by mutations in the VMA21 gene stand as exceptions, specifically affecting skeletal muscle (X-linked Myopathy with Excessive Autophagy, XMEA) or liver (Congenital Disorder of Glycosylation). VMA21 chaperones vacuolar (v-) ATPase assembly, which is ubiquitously required for proper lysosomal acidification.
View Article and Find Full Text PDFFollicular lymphoma-associated mutations in the V-ATPase chaperone VMA21 activate autophagy creating a targetable dependency.
Autophagy
August 2022
Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA.
The discovery of recurrent mutations in subunits and regulators of the vacuolar-type H-translocating ATPase (V-ATPase) in follicular lymphoma (FL) highlights a role for macroautophagy/autophagy, amino-acid, and nutrient-sensing pathways in the pathogenesis of this disease. Here, we report on novel mutations in the ER-resident chaperone VMA21, which is involved in V-ATPase assembly in 12% of FL. Mutations in a novel VMA21 hotspot (p.
View Article and Find Full Text PDFMutations in the V-ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease.
Hepatology
December 2020
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
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.
View Article and Find Full Text PDFAutophagic vacuolar pathology in desminopathies.
Neuromuscul Disord
March 2015
Department of Neurology and Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO, USA.
Autophagic vacuolar myopathies are an emerging group of muscle diseases with common pathologic features. These include autophagic vacuoles containing both lysosomal and autophagosomal proteins sometimes lined with sarcolemmal proteins such as dystrophin. These features have been most clearly described in patients with Danon's disease due to LAMP2 deficiency and X-linked myopathy with excessive autophagy (XMEA) due to mutations in VMA21.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!