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1- Department of Biology, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran.
2- Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Objective: The limb-girdle muscular dystrophies (LGMDs) are a diverse set of muscle disorders with several subgroups classified by disease gene and inheritance pattern. Numerous pathogenic mutations in calpain-3, the intracellular calcium-dependent protease encoded by the calcium-activated neutral proteinase 3 (CAPN3) gene, have been linked to an autosomal recessive type of this muscle disorder (LGMD2A), resulting in a weakened pelvic and shoulder girdle. This study aimed to investigate causative mutations in a consanguineous family with two afflicted offspring who were highly suspected of having LGMD.
Material and Methods: This study sought to find causal variations in a consanguineous family with two affected offspring strongly suspected of LGMD referred to our genetic department at Ahvaz Noorgene Genetic & Clinical Laboratory to diagnose their muscular dystrophy type. We applied whole-exome sequencing (WES) to find the causal variations in the proband's genomic DNA. We next performed confirmation and co-segregation analysis of the discovered variant with the phenotype in the proband and family members using Sanger sequencing.
Results: Following bioinformatic analysis and data filtering, we identified a homozygous variation, NM_000070.3:c.661G>T:p.G221C, within the CAPN3 gene that was validated by Sanger sequencing in the proband and segregated with LGMD2A in the family. The single alternation was described as pathogenic and regarded as a missense variant that altered protein features due to the replacement of the highly conserved amino acid Glycine in the catalytic domain of calpain-3 protein by a Cysteine.
Conclusion: The results of this investigation offer additional support for the genetic heterogeneity of LGMD and expand the mutational gene spectrum of CAPN3-associated muscular dystrophy by finding a pathogenic CAPN3 variant in both homozygous and heterozygous forms that had not previously been reported in these patients.
Type of Study: Original | Subject: Cellular and molecular Neuroscience
Received: 2023/12/2 | Accepted: 2024/02/10

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