Mutational Spectrum of CAPN3 with Genotype-Phenotype Correlations in Limb Girdle Muscular Dystrophy Type 2A/R1 (LGMD2A/LGMDR1) Patients in India

2021 ◽  
Vol 8 (1) ◽  
pp. 125-136
Author(s):  
Pankaj Pathak ◽  
Mehar Chand Sharma ◽  
Pankaj Jha ◽  
Chitra Sarkar ◽  
Mohammed Faruq ◽  
...  

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.

10.1038/10579 ◽  
1999 ◽  
Vol 5 (7) ◽  
pp. 849-849 ◽  
Author(s):  
S. Baghdiguian ◽  
M. Martin ◽  
I. Richard ◽  
F. Pons ◽  
C. Astier ◽  
...  

2011 ◽  
Vol 20 (17) ◽  
pp. 3331-3345 ◽  
Author(s):  
Natalia Ermolova ◽  
Elena Kudryashova ◽  
Marino DiFranco ◽  
Julio Vergara ◽  
Irina Kramerova ◽  
...  

2015 ◽  
Vol 17 (2) ◽  
pp. 59-62 ◽  
Author(s):  
Edwardo Ramos ◽  
Sherly Pardo ◽  
Manuel F. Mas Rodríguez ◽  
John Vélez

2000 ◽  
Vol 10 (8) ◽  
pp. 553-559 ◽  
Author(s):  
Louise V.B Anderson ◽  
Ruth M Harrison ◽  
Robert Pogue ◽  
Elizabeth Vafiadaki ◽  
Christine Pollitt ◽  
...  

2001 ◽  
Vol 11 (6-7) ◽  
pp. 547-555 ◽  
Author(s):  
Jonghee Chae ◽  
Narihiro Minami ◽  
Yuko Jin ◽  
Masahiro Nakagawa ◽  
Kumiko Murayama ◽  
...  

Cell Calcium ◽  
2009 ◽  
Vol 46 (5-6) ◽  
pp. 356-363 ◽  
Author(s):  
Ilenia Bertipaglia ◽  
Natalie Bourg ◽  
Isabelle Richard ◽  
Anna-Karin Pahlman ◽  
Liselotte Andersson ◽  
...  

2017 ◽  
Vol 3 (2) ◽  
pp. 26
Author(s):  
Nydia Rena Benita Sihombing ◽  
Nurin Aisyiyah Listyasari ◽  
Sultana MH Faradz

ABSTRACTBackground: Limb girdle muscular dystrophy (LGMD) is a neuromuscular abnormality with clinical heterogeneity and various severity, where over 30 subtypes have been identified. Meanwhile, molecular diagnosis of LGMD is not commonly carried out in Indonesia. We present a large pedigree of familial LGMD, with over 14 years of follow-up.Case Presentation: A 12-year old female patient came with muscle weakness. She had toe walking since age of 6, followed by calf hypertrophy for over three years. Family history revealed complex consanguinity. Her younger sister and her parents’ cousin had similar condition, with the latter was already bedridden.Physical examination results were waddling gait, lordotic spine, and absent deep tendon reflexes. Muscle biopsy showed sign of dystrophic process. Immunoperoxidase staining of some proteins resulted normal. Single nucleotide polymorphism (SNP) array in two siblings revealed homozygosity on chromosome 15 containing CAPN3 gene of LGMD2A subtype.Recently, the patient is wheelchair bound and undergoes rehabilitation. Her sister is still able to walk with abnormal gait, while her parents’ cousin had passed away in age 55. From the multiple consanguinity, it could be concluded as autosomal recessive type LGMD.Conclusion: A large family with LGMD from Indonesia was presented with more than 14 years of care. Clinical diagnosis was made based on physical and additional examination, however molecular analysis for establishing definitive diagnosis is still limited. Further studies such as targeted or whole exome sequencing is warranted to elucidate the cause of disease. Long-term evaluation and supportive care, in addition to proper counseling may increase quality of life.


Cell ◽  
1995 ◽  
Vol 81 (1) ◽  
pp. 27-40 ◽  
Author(s):  
Isabelle Richard ◽  
Odile Broux ◽  
Valéerie Allamand ◽  
Françoise Fougerousse ◽  
Nuchanard Chiannilkulchai ◽  
...  

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