580P SYNE-1 and SYNE-2 Mutations: Expanding the Phenotype and Genotype Spectrum of Nesprin Myopathy

Nesprins are a family of spectrin-repeat proteins located at the nuclear envelope which play an important role in nuclear morphology and mechano-transduction. Nesprin-1 and Nesprin-2, encoded by the synaptic nuclear envelope SYNE1 and SYNE2, are highly expressed in cardiac and skeletal muscle. Mutations in SYNE1 have been associated with the autosomal dominant Emery‐Dreifuss Muscular Dystrophy (EDMD) type 4, Congenital Muscular Dystrophy, and Arthrogryposis Multiplex Congenita while mutations in SYNE2 only with Emery‐Dreifuss muscular dystrophy type 5. In this study, we aimed at defining the clinical characteristics, histopathological features and molecular profile of 54 patients carrying single nucleotide variants in SYNE1 and SYNE2 genes. Multiple algorithms were used to predict the deleteriousness of the variants and only variants with Combined Annotation Dependent Depletion (CADD) scores ≥20 were selected. In our cohort 56% of patients were women; 60% of patients had late onset myopathy and 23% of patients presented with EDMD-like phenotype. In 80% of patients muscle biopsy showed myopathic signs, with dystrophic changes in the 28% of cases. The subcellular localization of Nesprin-1 and -2 and their co-localization with Emerin, an inner nuclear membrane protein, were evaluated by immunofluorescence in muscle tissue from 21 patients and neither reduced nuclear staining nor mislocalization of both nesprins were detected. Our data provide a further insight into the clinical phenotypes and muscle pathology associated with SYNE1 or SYNE2 mutations and suggest that immunohistochemistry does not represent a useful diagnostic tool.