Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregates myopathy with synaptopathy - Archive ouverte HAL Accéder directement au contenu
Communication Dans Un Congrès Année : 2017

Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregates myopathy with synaptopathy

Résumé

Mutations in GFPT1 (glutamine-fructose-6-phosphate transaminase 1), a gene encoding an enzyme involved in glycosylation of ubiquitous proteins, cause a limb-girdle congenital myasthenic syndrome (LG-CMS) with tubular aggregates (TAs) characterized predominantly by affection of the proximal skeletal muscles and presence of highly organized and remodeled sarcoplasmic tubules in patients’ muscle biopsies. GFPT1 is the first and rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP) involved in ubiquitous glycosylation processes (Senderek J. et al., 2011). Since 2011, a total of 52 patients with GFPT1 mutations have been clinically reported (Guergueltcheva V. et al., 2012; Senderek et al., 2011;Selcen D. et al., 2013; Huh S-Y. et al., 2012). In this study, we report the retrospective clinical description and the molecular investigations of 11 individuals from 9 unrelated families with LG-CMS linked to recessively-inherited mutations in GFPT1. Interestingly, GFPT1 is expressed in various tissues, including skeletal muscle and motor nerve, raising the intriguing question of why mutations in such a ubiquitous gene would specifically lead to synaptic and muscular disorganization. In this study, we report here the first long-term clinical follow-up of 11 French individuals suffering from LG-CMS with TAs due to GFPT1 mutations, of which 9 are new. Our retrospective clinical evaluation stresses an evolution toward a myopathic weakness that occurs concomitantly to ineffectiveness of usual CMS treatments. Analysis of neuromuscular biopsies from 3 unrelated individuals demonstrates that the maintenance of neuromuscular junctions (NMJs) is dramatically impaired with loss of post-synaptic junctional folds and evidence of denervation-reinnervation processes affecting the 3 main NMJ components. Moreover, molecular analyses of the human muscle biopsies confirm glycosylation defects of proteins with reduced O-glycosylation and show reduced sialylation of transmembrane proteins in extrajunctional area. Altogether, these results pave the way for understanding the etiology of this rare neuromuscular disorder that may be considered as a “tubular aggregates myopathy with synaptopathy”
Fichier non déposé

Dates et versions

hal-03994005 , version 1 (17-02-2023)

Identifiants

  • HAL Id : hal-03994005 , version 1

Citer

Stéphanie Bauché, Geoffroy Vellieux, Damien Sternberg, Marie-Joséphine Fontenille, Guy Brochier, et al.. Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregates myopathy with synaptopathy. journées de la société française de myologie, Nov 2017, Colmar, France. ⟨hal-03994005⟩
18 Consultations
0 Téléchargements

Partager

Gmail Facebook X LinkedIn More