Ancestral founder mutations in calpain‐3 in the Indian Agarwal community: Historical, clinical, and molecular perspective

Ankala, Arunkanth; Kohn, Jaden R.; Dastur, Rashna S; Gaitonde, Pradnya S; Khadilkar, Satish V; Hegde, Madhuri

doi:10.1002/mus.23763

Cited by 29 publications

(28 citation statements)

References 29 publications

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“…For example, there are several founder mutations in the calpain 3 gene, reported from La Reunion Island,8 Northern Indiana,9 10 Basque country, Spain and Brazil,11–13 Japan,14–16 Venetian lagoon,17 Italian Alps18 and western India 19. The knowledge of regional prevalence and existence of founder mutations can help in reaching a quick genetic diagnosis.…”

Section: Clinical Approachmentioning

confidence: 99%

Making sense of the clinical spectrum of limb girdle muscular dystrophies

2018

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The expansion of the spectrum of limb girdle muscular dystrophies (LGMDs) in recent years means that neurologists need to be familiar with the clinical clues that can help with their diagnosis. The LGMDs comprise a group of genetic myopathies that manifest as chronic progressive weakness of hip and shoulder girdles. Their inheritance is either autosomal dominant (LGMD1) or autosomal recessive (LGMD2). Their prevalence varies in different regions of the world; certain ethnic groups have documented founder mutations and this knowledge can facilitate the diagnosis. The clinical approach to LGMDs uses the age at onset, genetic transmission and clinical patterns of muscular weakness. Helpful clinical features that help to differentiate the various subtypes include: predominant upper girdle weakness, disproportionate respiratory muscle involvement, distal weakness, hip adductor weakness, 'biceps lump' and 'diamond on quadriceps' sign, calf hypertrophy, contractures and cardiac involvement. Almost half of patients with LGMD have such clinical clues. Investigations such as serum creatine kinase, electrophysiology, muscle biopsy and genetic studies can complement the clinical examination. In this review, we discuss diagnostic clinical pointers and comment on the differential diagnosis and relevant investigations, using illustrative case studies.

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Section: Clinical Approachmentioning

confidence: 99%

Making sense of the clinical spectrum of limb girdle muscular dystrophies

2018

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“…[30] Founder effect for the c.550delA mutation has been demonstrated in the Eastern Mediterranean region (Russia, Croatia, Bulgaria, and Northern Italy)[313233343536373839404142] Other rare mutations which have a founder effect in small populations due to cultural inbreeding associated with historical, demographic, or religious factors have been reported in the population of La Reunion Island in the Indian Ocean (c.946-1G>A),[43] in the Old Order Amish community in Northern Indiana in the USA (c.2306G>A),[4445] in the Guipuzcoa region of the Basque Country of Spain and in Brazil (c.2362_2363delAGinsTCATCT),[464748] Japan (c.1795_1796insA),[495051] the Chioggia village in the Venetian lagoon (p.R490Q),[35] the Mocheni population in the Italian Alps (c.1193 + 6T>A),[52] and the Agarwal community in Northern India (p.D780H and c.2099-1G>T). [53] The last one is relevant to India and hence is discussed further.…”

Section: Calpainopathymentioning

confidence: 99%

Limb-girdle muscular dystrophies in India: A review

Khadilkar¹,

Faldu²,

Patil³

et al. 2017

Ann Indian Acad Neurol

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Limb-girdle muscular dystrophies (LGMDs) are common in India. Information on LGMDs has been gradually evolving in the recent years. This information is scattered in case series and case studies. The aim of this study is to collate available Indian information on LGMDs and put it in perspective. PubMed search using keywords such as limb-girdle muscular dystrophies in India, sarcoglycanopathies, dysferlinopathy, calpainopathy, and GNE myopathy was carried out. The published information on LGMDs in Indian context suggests that dysferlinopathy, calpainopathy, sarcoglycanopathies, and other myopathies such as GNE myopathy are frequently seen in India. Besides these, anecdotal reports of many other forms are available, some with genetic support and others showing immunocytochemical defects. The genotypic information on LGMDs is gradually evolving and founder mutations have been detected in selected populations. Further multicenter studies are necessary to document the incidence and prevalence of these common conditions in India.

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“…Both sequence variants exchange evolutionary conserved amino acids in domain IV of CAPN3 (exon 22), which may affect Ca 2+ -binding with downstream effects on autolytic activity. Interestingly, c.2338 G>C was inherited from his mother and is a recently recognized founder mutation originating from northern India in the Agarwal community, whose clan members practice intra-communal exogamy and are postulated to be descendants of King Agrasen [34]. This mutation was previously shown to cause pelvifemoral LGMD2A in the homozygous state and in combination with c.2099-1 G>T or c.1106 G>A, but effects on CAPN3 expression were inconclusive (protein non-significantly reduced vs. absent) [34], [35].…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, c.2338 G>C was inherited from his mother and is a recently recognized founder mutation originating from northern India in the Agarwal community, whose clan members practice intra-communal exogamy and are postulated to be descendants of King Agrasen [34]. This mutation was previously shown to cause pelvifemoral LGMD2A in the homozygous state and in combination with c.2099-1 G>T or c.1106 G>A, but effects on CAPN3 expression were inconclusive (protein non-significantly reduced vs. absent) [34], [35]. We speculate that the novel sequence variant c.2366 T>A has deleterious effects on protein expression and autolysis of CAPN3, although verification in a homozygous patient or through site-directed mutagenesis is preferred.…”

Section: Resultsmentioning

confidence: 99%

Redox State and Mitochondrial Respiratory Chain Function in Skeletal Muscle of LGMD2A Patients

et al. 2014

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BackgroundCalpain-3 deficiency causes oxidative and nitrosative stress-induced damage in skeletal muscle of LGMD2A patients, but mitochondrial respiratory chain function and anti-oxidant levels have not been systematically assessed in this clinical population previously.MethodsWe identified 14 patients with phenotypes consistent with LGMD2A and performed CAPN3 gene sequencing, CAPN3 expression/autolysis measurements, and in silico predictions of pathogenicity. Oxidative damage, anti-oxidant capacity, and mitochondrial enzyme activities were determined in a subset of muscle biopsies.ResultsTwenty-one disease-causing variants were detected along the entire CAPN3 gene, five of which were novel (c.338 T>C, c.500 T>C, c.1525-1 G>T, c.2115+4 T>G, c.2366 T>A). Protein- and mRNA-based tests confirmed in silico predictions and the clinical diagnosis in 75% of patients. Reductions in antioxidant defense mechanisms (SOD-1 and NRF-2, but not SOD-2), coupled with increased lipid peroxidation and protein ubiquitination, were observed in calpain-3 deficient muscle, indicating a redox imbalance primarily affecting non-mitochondrial compartments. Although ATP synthase levels were significantly lower in LGMD2A patients, citrate synthase, cytochrome c oxidase, and complex I+III activities were not different from controls.ConclusionsDespite significant oxidative damage and redox imbalance in cytosolic/myofibrillar compartments, mitochondrial respiratory chain function is largely maintained in skeletal muscle of LGMD2A patients.

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Ancestral founder mutations in calpain‐3 in the Indian Agarwal community: Historical, clinical, and molecular perspective

Abstract: Founder mutations have immediate clinical application, at least in selected population groups. Clinically available gene panels may provide a definitive molecular diagnosis for heterogeneous disorders such as LGMD.

Cited by 29 publications

References 29 publications

Making sense of the clinical spectrum of limb girdle muscular dystrophies

Making sense of the clinical spectrum of limb girdle muscular dystrophies

Limb-girdle muscular dystrophies in India: A review

Redox State and Mitochondrial Respiratory Chain Function in Skeletal Muscle of LGMD2A Patients

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