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

被引:3
|
作者
Pathak, Pankaj [1 ,6 ,7 ]
Sharma, Mehar Chand [1 ]
Jha, Pankaj [2 ]
Sarkar, Chitra [1 ]
Faruq, Mohammed [2 ]
Jha, Prerana [1 ]
Suri, Vaishali [1 ]
Bhatia, Rohit [3 ]
Singh, Sumit [4 ]
Gulati, Sheffali [5 ]
Husain, Mohammad [6 ]
机构
[1] All India Inst Med Sci, Dept Pathol, New Delhi 110029, India
[2] CSIR Inst Genom & Integrat Biol, New Delhi, India
[3] All India Inst Med Sci, Dept Neurol, New Delhi, India
[4] Medanta, Dept Neurol, Gurgaon, Haryana, India
[5] All India Inst Med Sci, Dept Paediat Neurol, New Delhi, India
[6] Jamia Millia Islamia, Dept Biotechnol, New Delhi, India
[7] NINDS, Neurogenet Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA
关键词
LGMD2A; LGMDR1; CAPN3; LGMD; calpain-3; muscular dystrophy; calpainopathy; autosomal recessive; immunoblot; CALPAIN; 3; GENE; FOUNDER MUTATIONS; LGMD2A PATIENTS; PROTEIN; DIAGNOSIS; DELETION; 2A; VARIABILITY; EXPRESSION; FREQUENCY;
D O I
10.3233/JND-200547
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
引用
收藏
页码:125 / 136
页数:12
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