Back to Search
Start Over
Mutational Spectrum of CAPN3 with Genotype-Phenotype Correlations in Limb Girdle Muscular Dystrophy Type 2A/R1 (LGMD2A/LGMDR1) Patients in India
- Source :
- Journal of Neuromuscular Diseases. 8:125-136
- Publication Year :
- 2021
- Publisher :
- IOS Press, 2021.
-
Abstract
- Background: Limb girdle muscular dystrophy recessive type 1 (LGMDR1, Previously LGMD2A) is characterized by inactivating mutations in CAPN3. Despite the significant burden of muscular dystrophy in India, and particularly of LGMDR1, its genetic characterization and possible phenotypic manifestations are yet unidentified. Material and Methods: We performed bidirectional CAPN3 sequencing in 95 LGMDR1 patient samples characterized by calpain-3 protein analysis, and these findings were correlated with clinical, biochemical and histopathological features. Results: We identified 84 (88.4%) cases of LGMDR1 harboring 103 CAPN3 mutations (71 novel and 32 known). At least two mutant alleles were identified in 79 (94.2%) of patients. Notably, 76% exonic variations were enriched in nine CAPN3 exons and overall, 41 variations (40%) correspond to only eight exonic and intronic mutations. Patients with two nonsense/out of frame/splice-site mutations showed significant loss of calpain-3 protein as compared to those with two missense/inframe mutations (P = 0.04). We observed a slow progression of disease and less severity in our patients compared to European population. Rarely, presenting clinical features were atypical, and mimicked other muscle diseases like FSHMD, distal myopathy and metabolic myopathies. Conclusion: This is first systematic study to characterize the genetic framework of LGMDR1 in the Indian population. Preliminary calpain-3 immunoblot screening serves well to direct genetic testing. Our findings prioritized nine CAPN3 exons for LGMDR1 diagnosis in our population; therefore, a targeted-sequencing panel of nine exons could serve well for genetic diagnosis, carrier testing, counseling and clinical trial feasibility study in LGMDR1 patients in India.
- Subjects :
- Population
India
Muscle Proteins
Biology
Carrier testing
medicine
Humans
Missense mutation
Genetic Testing
Muscular dystrophy
Allele
education
Myopathy
Genetic Association Studies
Genetic testing
Genetics
education.field_of_study
medicine.diagnostic_test
Calpain
Sequence Analysis, DNA
medicine.disease
Muscular Dystrophies, Limb-Girdle
Neurology
Mutation
Neurology (clinical)
medicine.symptom
Limb-girdle muscular dystrophy
Subjects
Details
- ISSN :
- 22143602 and 22143599
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Journal of Neuromuscular Diseases
- Accession number :
- edsair.doi.dedup.....cc03568c391c2d8857236513594c7ad0
- Full Text :
- https://doi.org/10.3233/jnd-200547