Desmin Geni C.1289-2a>G Mutasyonunun Desmin Proteinine Etkisinin İncelenmesi
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Autosomal recessive limb girdle muscular dystrophy (LGMD2) is clinically and genetically heterogeneous group of diseases that are characterized by progressive atrophy and weakness of proximal muscles. Two siblings of a consanguineous marriage are diagnosed LGMD2 according to clinical and histopatological findings. In this thesis study, c.1289-2A>G splice site mutation on desmin gene is determined in these two siblings diagnosed with LGMD2. The mutation in the desmin gene, defined for the first time, causes in-frame insertion of 48 bp to RNA sequence and insertion of 16 amino acids a to protein sequence in tail domain following 428th residue. The identical mutation was also detected in single allele of both parents, who both were healthy. Illustrating the desmin protein expression in the index case, led us to conclusion that c.1289-2A>G splice site mutation doesn?t cause loss of function of desmin protein. As a result of the electron microscopy and histopathological examination of the muscle biopsy specimens no sliding on Z-discs was detected and no intracellular deposits were observed, which led us to conclusion that the physiopathology is a consequence of the disruption of protein-protein interactions. According to previous literature data, insertion of 16 amino acids a to desmin protein sequence in tail domain following 428. residue, results in removal of lamin B binding region of desmin protein. To display desmin-lamin B interaction, double-labelled immunfloresance staining followed by confocal microscopy examination was performed, desmin and lamin B interaction was shown to be destroyed. Although the loss of interaction does not lead to a deformation in nuclear morphology, it impairs the nuclear-sarcoplasmic connection; therefore we propose that this impairment weakens muscle resistance against shear stress, which consecutively results in muscle degeneration.