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 Sypniewski; Birute Burnyte; Baiba Lace

doi:10.1002/humu.24421

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

Neurology

Research output: Contribution to journal › Article › Academic › peer-review

5 Citations (Scopus)

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 language	English
Pages (from-to)	1347-1353
Number of pages	7
Journal	Human Mutation
Volume	43
Issue number	10
DOIs	https://doi.org/10.1002/humu.24421
Publication status	Published - 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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Mroczek, M., Inashkina, I., Stavusis, J., Zayakin, P., Khrunin, A., Micule, I., Kenina, V., Zdanovica, A., Zídková, J., Fajkusová, L., Limborska, S., van der Kooi, A. J., Brusse, E., Leonardis, L., Maver, A., Pajusalu, S., Õunap, K., Puusepp, S., Dobosz, P., ... Lace, B. (2022). CAPN3 c.1746-20C>G variant is hypomorphic for LGMD R1 calpain 3-related. Human Mutation, 43(10), 1347-1353. https://doi.org/10.1002/humu.24421

@article{b376b31c23ab40e78da709b0bc94a2c4,

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

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.",

author = "Magdalena Mroczek and Inna Inashkina and Janis Stavusis and Pawel Zayakin and Andrey Khrunin and Ieva Micule and Victorija Kenina and Anna Zdanovica and Jana Z{\'i}dkov{\'a} and Lenka Fajkusov{\'a} and Svetlana Limborska and {van der Kooi}, {Anneke J.} and Esther Brusse and Lea Leonardis and Ales Maver and Sander Pajusalu and Katrin {\~O}unap and Sanna Puusepp and Paula Dobosz and Mateusz Sypniewski and Birute Burnyte and Baiba Lace",

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: {\textcopyright} 2022 Wiley Periodicals LLC.",

year = "2022",

month = oct,

doi = "10.1002/humu.24421",

language = "English",

volume = "43",

pages = "1347--1353",

journal = "Human Mutation",

issn = "1059-7794",

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Mroczek, M, Inashkina, I, Stavusis, J, Zayakin, P, Khrunin, A, Micule, I, Kenina, V, Zdanovica, A, Zídková, J, Fajkusová, L, Limborska, S, van der Kooi, AJ, Brusse, E, Leonardis, L, Maver, A, Pajusalu, S, Õunap, K, Puusepp, S, Dobosz, P, Sypniewski, M, Burnyte, B & Lace, B 2022, 'CAPN3 c.1746-20C>G variant is hypomorphic for LGMD R1 calpain 3-related', Human Mutation, vol. 43, no. 10, pp. 1347-1353. https://doi.org/10.1002/humu.24421

TY - JOUR

T1 - CAPN3 c.1746-20C>G variant is hypomorphic for LGMD R1 calpain 3-related

AU - Mroczek, Magdalena

AU - Inashkina, Inna

AU - Stavusis, Janis

AU - Zayakin, Pawel

AU - Khrunin, Andrey

AU - Micule, Ieva

AU - Kenina, Victorija

AU - Zdanovica, Anna

AU - Zídková, Jana

AU - Fajkusová, Lenka

AU - Limborska, Svetlana

AU - van der Kooi, Anneke J.

AU - Brusse, Esther

AU - Leonardis, Lea

AU - Maver, Ales

AU - Pajusalu, Sander

AU - Õunap, Katrin

AU - Puusepp, Sanna

AU - Dobosz, Paula

AU - Sypniewski, Mateusz

AU - Burnyte, Birute

AU - Lace, Baiba

N1 - 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.

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

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U2 - 10.1002/humu.24421

DO - 10.1002/humu.24421

M3 - Article

C2 - 35731190

AN - SCOPUS:85132317495

SN - 1059-7794

VL - 43

SP - 1347

EP - 1353

JO - Human Mutation

JF - Human Mutation

IS - 10

ER -

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

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