Understanding the clinical spectrum associated with VMA21 deficiency
Prof. Perrine Castets, University of Geneva
Abstract
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.
Projets
- Nouveaux projets de recherche dès 2024
- L'importance de la recherche
- Projets financés
- Unstructured proteins as therapeutic targets for neuromuscular diseases
- Open and reproducible pipeline for the acquisition and analysis of muscle MRI data in Facioscapulohumeral Muscular Dystrophy
- Dissecting lysosomal signals to fight Pompe disease
- Functional properties and epigenetic signature of quiescent and early activated human muscle reserve cells
- Activation of human skeletal muscle stem cells:role of Orai3 ans its partner AHNAK2 in physiological condition and in Duchenne Muscular Dystrophy
- Understanding the clinical spectrum associated with VMA21 deficiency
- ANTXR2 as a key player in Collagen VI signaling in muscle stem cells: new therapeutic perspectives for COL6-related myopathies.
- Molecular mechanisms of complement activation and neuromuscular disruption by combinations of autoantibodies from patients with Myasthenia Gravis
- From the investigation of the role of SRSF1 in ALS/FTD to its targeting as a therapeutic strategy
- Molecular crosstalk between muscles and motor neurons and its role in neuromuscular circuit formation
- Molecular Diagnosis and Coping Mechanisms in Mitochondrial Myopathies
- IPRIMYO: Immune-privileged, immortal, myogenic stem cells for gene therapy of Muscular Dystrophy
- Effect of RYR1 mutations on muscle spindle function and their impact on the musculoskeletal system
- Therapeutic potential of human myogenic reserve cells in Duchenne Muscular Dystrophy
- Glutamine metabolism as a potential target for Duchenne Muscular Dystrophy
- Targeting protein s-acylation during Tubular Aggregate Myopathy
- Aggravating the phenotype of dystrophic mice for improving preclinical research and clinical translation for Duchenne muscular dystrophy
- Characterization of autoreactive T cells in Guillain-Barré syndrome
- A vascularized human muscle-on-a-chip to elucidate the contribution of endothelial-mesenchymal transition on the progression of muscular dystrophies
- Characterization of a novel form of ALS associated with changes in the sphingolipid metabolism
- Pre-clinical treatment of mouse models carrying recessive Ryr1 mutations with HDAC/DNA methyltransferase inhibitors.
- New aspects of TGFβ signaling in muscle homeostasis and regeneration
- Inhibition of sphingolipid synthesis as a treatment strategy for Duchenne muscular dystrophy
- Tamoxifen in Duchenne muscular dystrophy (TAMDMD)
- DNA aptamers against the DUX4 protein reveal novel therapeutic implications for FSHD
- Facilitating diagnosis of critical illness myopathy using muscle excitability testing
- Rapid Exploratory Imaging for High-resolution and Whole Extremity Coverage in MR Neurography
- Deciphering novel mechanisms and effectors contributing to muscle dysfunction in Myotonic Dystrophy Type I
- Can HDAC/DNA methyltransferase inhibitors improve muscle function in a congenital myopathy caused by recessive RYR1 mutations?
- Identification of the critical regulators of protein synthesis and degradation in human muscle atrophy
- Exploring peripheral B-cell-helper T cell phenotypes in the blood of patients with Myasthenia gravis using mass cytometry (CyTOF)
- Molecular signature, metabolic profile and therapeutic potential of human myogenic reserve cells
- A multicenter cross-sectional and longitudinal study of the Swiss cohort of Merosin-negative congenital muscular dystrophy
- Targeting NADPH oxidase 4 in models of Duchenne muscular dystrophy
- Characterizing the role of ER stress in C9orf72-linked ALS pathology
- Inducing mitophagy with Urolithin A to restore mitochondrial and muscle function in muscular dystrophy
- Motor unit action potentials analysis in patients with myopathies with a new wireless portable and multichannel Surface EMG device (WPM-SEMG)
- Role and therapeutic potential of PLIN3 in neuromuscular diseases
- Changes in ventilation distribution in children with neuromuscular disease using the insufflator/exsufflator technique: An observational study
- Mechanism and function of genome organization in muscle development and integrity
- Role and therapeutic potential of NADPH oxidases in a mouse model of Duchenne Muscular Dystrophy
- Characterization of pathological pathways activated in muscles of patients with congenital myopathies with disturbed Ca2+ homeostasis
- Creation of a study team to conduct an SMA 1-clinical trial at the Centre for Neuromuscular Diseases of the University Children's Hospital Basel (UKBB)
- Novel treatment to stop progressive neuropathy and muscle weakness in multifocal motor neuropathy
- Understanding the pathomechanisms leading to muscle alterations in Myotonic Dystrophy type I
- Automated volumetry and quantitative MRI to diagnose peripheral nerve lesions – translational proposal for a new clinical diagnostic imaging tool
- Novel approaches against Spinal Muscular Atrophy by targeting splicing regulators
- Protective effects and mechanisms of action of tamoxifen in mice with severe muscular diseases
- Role of the receptor FgfrL1 in the development of slow muscle fibers
- Muscle velocity recovery cycles: A new tool for early diagnosis of critical illness myopathy
- Generation of uncommitted human IPSC derived muscle stem cells for therapeutic applications
- Transposable vectors for dystrophin-expression in a murine model for muscular dystrophy
- Cardiac involvement in patients with Duchenne/Becker Muscular Dystrophy; an observational study
- Deciphering the pathogenic mechanisms of C9ORF72 ALS
- Enhancing estrogenic signalling to fight muscular dystrophies: Mechanisms of action and repurposing clinically approved drugs
- Mechanisms and therapeutic potential of modulating PGC‐1α to alter neuromuscular junction morphology and function
- Triggering human myoblast differentiation: from EGFR to myogenic transcription factors
- Improving cellular therapies of muscle dystrophies by uncovering epigenetic and signaling pathways of muscle formation
- Protein engineering in an attempt to increase the mechanical, integrin dependent cytoskeleton-matrix linkage in muscle fibers
- Muscle velocity recovery cycles: a new tool for characterization of muscle disease in vivo
- Excessive neurotrypsin activation and agrin cleavage-a pathogenic condition leading to sarcopenia-like muscle atrophy?
- Evaluation of novel treatment strategies for dyspherlinopathies in mouse models
- Cell therapy of LGMD2D by donor HLA-characterized human mesoangioblasts (hMABs) produced in GMP conditions
- In search of small molecules targeting protein-RNA complex: a novel approach against Spinal Muscular Atrophy
- Restoration of autophagy as a new strategy for the treatment of congenital muscular dystrophies
- Development of magnetic resonance methods for functional imaging of the skeletal muscle
- Targeting ER stress response: a potential mechanism for neuroprotection in Amyotrophic Lateral Sclerosis
- Generation of uncommitted human IPSC derived muscle stem cells for therapeutic applications
- Brochure décrivant les projets
- SEAL Therapeutics AG
- Rencontres et séminaires
- Participation à des associations faîtières
- Les registres de patients
- Le réseau Myosuisse
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- philippe.rognon@fsrmm.ch