Understanding the clinical spectrum associated with VMA21 deficiency

Prof. Perrine Castets, University of Geneva


X-linked myopathy with excessive autophagy (XMEA) is a rare neuromuscular disease characterized by progressive muscle atrophy and weakness, and caused by mutations in the VMA21 gene. Recently, mutations in VMA21 have also been associated with a congenital autophagic liver disease, as well as with lymphoma. The reason for the dysfunction of specific tissues and the protection of other organs, dependent on the disease is unknown. VMA21 encodes a ubiquitous chaperone protein essential for the assembly of the vacuolar ATPase, required for lysosomal acidification. Consistently, VMA21 deficiency leads to autophagy impairment in patient cells. However, the mechanisms leading to muscle or liver dysfunction remain misunderstood, which largely falls to the absence of a mouse model reproducing VMA21 deficiency. We have recently generated a muscle-specific Vma21-KO mouse line, which brought major insights on XMEA pathogenesis. However, this model has two limitations: 1) its early lethality hampers investigations in adult muscle, 2) the effect of VMA21 deficiency in non-muscle tissue cannot be analyzed. The overall aim of the project is to get insights on the pathomechanisms leading to VMA21-related disorders and to test therapeutic strategies to counteract the diseases, by developing two new VMA21-deficient mouse lines. Specifically, we will develop an inducible muscle-specific KO mouse model to characterize the consequences of VMA21 deficiency in adult muscle. We will determine if the mice reproduce XMEA and characterize their phenotype at different ages. The autophagic flux and associated signaling will be examined. In parallel, the generation of an inducible complete KO model will help delineating the role of VMA21 in muscles and non-muscle tissues during development and adult ages. In particular, it may bring essential insights on pathomechanisms leading to severe neonatal XMEA cases and it may point to compensatory processes protecting spared tissues in the absence of VMA21. Altogether, these experiments are essential to better understand the clinical spectrum associated with VMA21 mutations and to identify potential targets to circumvent VMA21-related disorders.