CAPN3 c.1746-20C>G variant is hypomorphic for LGMD R1 calpain 3-related

Magdalena Mroczek, Inna Inashkina, Janis Stavusis, Pawel Zayakin, Andrey Khrunin, Ieva Micule, Victorija Kenina, Anna Zdanovica, Jana Zídková, Lenka Fajkusová, Svetlana Limborska, Anneke J. van der Kooi, Esther Brusse, Lea Leonardis, Ales Maver, Sander Pajusalu, Katrin Õunap, Sanna Puusepp, Paula Dobosz, Mateusz SypniewskiBirute Burnyte, Baiba Lace*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1347-1353
Number of pages7
JournalHuman Mutation
Volume43
Issue number10
DOIs
Publication statusPublished - Oct 2022

Bibliographical note

ACKNOWLEDGEMENTS:
We thank Leroy Ten Dam and Pervin Dincer for the information regarding the homozygous patients from their cohorts. This work was supported by European Regional Development Fund (No. 1.1.1.1/18/A/096 “The determination of rare inherited diseases' causative mechanisms using whole genome sequencing approach”). We acknowledge support from the Estonian Research Council grants PRG471 and MOBTP175, the Russian Foundation for Basic Research (Grant No.: 20‐04‐00824) to Andrey Khrunin, and the Ministry of Health of the Czech Republic (FNB RVO 65269705).

Publisher Copyright: © 2022 Wiley Periodicals LLC.

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