Identification of a new splice site mutation in synaptotagmin-2 responsible for a severe and early presynaptic form of congenital myasthenic syndrome

International audienceCongenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of inherited disorders caused by defective synaptic transmission at the neuromuscular junction (NMJ) and characterized by fluctuation of muscle weakness and fatigability. Recently, many mutations encoding presynaptic and ubiquitous proteins have been identified as responsible for increasingly complex CMS phenotypes of CMS. Among them, this is the case of autosomal dominant mutations in Synaptotagmin2 (SYT2) C2B domain that have been linked to described as responsible for presynaptic CMS combined to Lambert-Eaton myasthenic syndromes and motor neuropathy forms. SYT2 is the major synaptotagmin isoform expressed at the NMJ and acts as a calcium sensor that is mediated by the presence of two tandem C2 domains. In the French cohort of CMS patients, we recently identified in a consanguineous family a new homozygote recessive intronic mutation in SYT2 causing an early and severe presynaptic CMS. Using a minigene construct we demonstrated that this intronic mutation in the donor splice site of SYT2 intron 4 leads to a SYT2 in-frame exon 4 skipping suppressing the N-terminal part of C2A domain. Morphological and functional studies revealed that defects in SYT2 C2A domain affects NMJs maintenance, synaptic transmission and triggers a decrease of SYT2 expression partially compensated by the upregulation of SYT1 expression at the NMJ. This study reports the identification of a new severe presynaptic CMS form associated to a recessive intronic mutation in SYT2 and completes the previously reported data on the dominant SYT2-related motor neuropathy and Lambert-Eaton myasthenic syndrome