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CAPN3 c.1746-20C>G variant is hypomorphic for LGMD R1 calpain 3-related.
Magdalena Mroczek1, Inna Inashkina2, Janis Stavusis2
1Department of Neurology and Neurophysiology, Balgrist University Hospital, University of Zurich, Zürich, Switzerland.
Human Mutation
|June 22, 2022
Summary
A common intronic CAPN3 variant (c.1746-20C>G) is reclassified as hypomorphic, explaining mild limb-girdle muscular dystrophy R1 cases in Eastern Europe. This variant reduces gene expression, impacting patients with compound heterozygous mutations.
Area of Science:
- Genetics and Molecular Biology
- Neuromuscular Disorders
Background:
- The intronic CAPN3 variant c.1746-20C>G is prevalent in Central and Eastern Europe (>1%) but has conflicting pathogenicity interpretations.
- Calpainopathy, specifically limb-girdle muscular dystrophy R1 (LGMD R1), is linked to mutations in the CAPN3 gene.
Purpose of the Study:
- To investigate the pathogenicity of the intronic CAPN3 variant c.1746-20C>G.
- To reclassify the variant based on clinical and molecular data.
- To explain previously unidentified LGMD R1 cases in Eastern and Central Europe.
Main Methods:
- Clinical data collection from 14 patients compound heterozygous for c.1746-20C>G and another pathogenic CAPN3 variant.
- Molecular studies analyzing splicing isoforms in muscle tissue.
- Variant reclassification based on gathered evidence.
Main Results:
- Patients compound heterozygous for c.1746-20C>G exhibited mild to medium severity calpainopathy.
- Molecular analysis revealed the production of diverse splicing isoforms in muscle.
- The variant is hypothesized to be hypomorphic, reducing RNA and protein expression.
Conclusions:
- The CAPN3 variant c.1746-20C>G is reclassified as a hypomorphic variant.
- This reclassification helps identify numerous previously unexplained LGMD R1 cases in Eastern and Central Europe.
- The variant's impact is likely dependent on the ratio of abnormal splicing isoforms.
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