Human mutation · 2022
CAPN3 c.1746-20C>G variant is hypomorphic for LGMD R1 calpain 3-related.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Mroczek Magdalena, Inashkina Inna, Stavusis Janis, Zayakin Pawel, Khrunin Andrey, Micule Ieva, Kenina Victorija, Zdanovica Anna, Zídková Jana, Fajkusová Lenka, Limborska Svetlana, van der Kooi Anneke J, Brusse Esther, Leonardis Lea, Maver Ales, Pajusalu Sander, Õunap Katrin, Puusepp Sanna, Dobosz Paula, Sypniewski Mateusz, Burnyte Birute, Lace Baiba
Аннотация
The investigated intronic CAPN3 variant NM_000070.3:c.1746-20C>G occurs in the Central and Eastern Europe with a frequency of >1% and there are conflicting interpretations on its pathogenicity. We collected data on 14 patients carrying the CAPN3 c.1746-20C>G variant in trans position with another CAPN3 pathogenic/likely pathogenic variant. The patients compound heterozygous for the CAPN3 c.1746-20C>G variant presented a phenotype consistent with calpainopathy of mild/medium severity. This variant is most frequent in the North/West regions of Russia and may originate from that area. Molecular studies revealed that different splicing isoforms are produced in the muscle. We hypothesize that c.1746-20C>G is a hypomorphic variant with a reduction of RNA and protein expression and only individuals having a higher ratio of abnormal isoforms are affected. Reclassification of the CAPN3 variant c.1746-20C>G from variant with a conflicting interpretation of pathogenicity to hypomorphic variant explains many unidentified cases of limb girdle muscular dystrophy R1 calpain 3-related in Eastern and Central Europe.