Volume 15, Issue 6 (November & December 2024)
BCN 2024, 15(6): 865-876 |
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Sakhaei A, Mohammadi-Asl J. Pathogenic CAPN3 Variant Identified in an Iranian Family With Limb-girdle Muscular Dystrophy. BCN 2024; 15 (6) :865-876
URL: http://bcn.iums.ac.ir/article-1-2833-en.html
URL: http://bcn.iums.ac.ir/article-1-2833-en.html
1- Department of Genetics, 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.
2- Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Abstract:
Introduction: Limb-girdle muscular dystrophies (LGMDs) are a diverse set of muscle disorders with several subgroups classified by defective genes and inheritance patterns. 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.
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 and 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. Then, we sought confirmation and performed a 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 replacing the highly conserved amino acid glycine in the catalytic domain of calpain-3 protein with 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.
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 and 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. Then, we sought confirmation and performed a 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 replacing the highly conserved amino acid glycine in the catalytic domain of calpain-3 protein with 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.
Keywords: Limb-girdle muscular dystrophy (LGMDs) type 2A, Whole-exome sequencing (WES), Calpain-3, Missense variant
Type of Study: Original |
Subject:
Cellular and molecular Neuroscience
Received: 2023/12/2 | Accepted: 2024/02/10 | Published: 2025/11/28
Received: 2023/12/2 | Accepted: 2024/02/10 | Published: 2025/11/28
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