A NEW CYS1678TYR MUTATION RESPONSIBLE OF LGMD2B IDENTIFIED IN A FAMILY FROM SOUTHERN ITALY

Background and Aims:: Mutations in the gene DYSF encoding dysferlin are responsible for dysferlinopathies. Dysferlin is mainly expressed in cardiac and skeletal muscle and appears to play an important role in the repair of the plasmalemma. Intra- and inter-family phenotypic variability has been reported in the literature for mutations in the DYSF gene. A new Cys1678Tyr mutation responsible of LGMD2B has been identified in a family from southern Italy. Methods:: Genomic DNA was extracted from peripheral blood lymphocytes of all family's affected and unaffected subjects using standard protocol. We developed a panel comprising 40 genes involved in LGMDs. The sequencing process was conducted on Ion Torrent PGM platform, annotation of variant calling by WANNOVAR. All the variations founded were confirmed by direct resequencing ABI PRISM 3130xl Genetic Analyzer. Results:: Molecular analysis of three patients from a southern Italian family allowed the identification of a new G5036A mutation in the DYSF gene responsible for LGMD 2B. This mutation determining the replacement of a cysteine in position 1678 with a tyrosine predicted to be deleterious by PolyPhen and silico SIFT analysis. Moreover, Swiss model pipeline analysis showed that this mutation causes the breaking of a strong disulfide bridge with important consequences on the protein activity. Conclusions:: The identification of new mutations responsible for LGMD2B and the study of several affected families will contribute to the identification of additional genetic, epigenetic, environmental factors responsible for the intra and inter-family variability reported in the literature. Furthermore, this will determine the development of new therapeutic targets and personalized medicine.