CAPN3 c.1746‐20C>G variant is hypomorphic for LGMD R1 calpain 3‐related
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 a...
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| Veröffentlicht in: | Human mutation 2022-10, Vol.43 (10), p.1347-1353 |
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| creator | Mroczek, Magdalena Inashkina, Inna Stavusis, Janis Zayakin, Pawel Khrunin, Andrey Micule, Ieva Kenina, Victorija Zdanovica, Anna Zídková, Jana Fajkusová, Lenka Limborska, Svetlana Kooi, Anneke J. Brusse, Esther Leonardis, Lea Maver, Ales Pajusalu, Sander Õunap, Katrin Puusepp, Sanna Dobosz, Paula Sypniewski, Mateusz Burnyte, Birute Lace, Baiba |
| description | 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.
Variant c.1746‐20C>G is a hypomorphic allele, associated with LGMD R1 calpain3‐related. |
| doi_str_mv | 10.1002/humu.24421 |
| format | Article |
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Variant c.1746‐20C>G is a hypomorphic allele, associated with LGMD R1 calpain3‐related.</description><identifier>ISSN: 1059-7794</identifier><identifier>EISSN: 1098-1004</identifier><identifier>DOI: 10.1002/humu.24421</identifier><language>eng</language><publisher>Hoboken: Hindawi Limited</publisher><subject>Alternative splicing ; Calpain ; calpainopathy ; CAPN3 ; hypomorphic variant ; Isoforms ; LGMD ; LGMD R1 calpain 3‐related ; Muscular dystrophy ; Pathogenicity ; Phenotypes ; Reclassification</subject><ispartof>Human mutation, 2022-10, Vol.43 (10), p.1347-1353</ispartof><rights>2022 Wiley Periodicals LLC.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c2851-c09dd6831362ed954ccda9006abbc942410667fc558ad6f9c5d51519447451463</citedby><cites>FETCH-LOGICAL-c2851-c09dd6831362ed954ccda9006abbc942410667fc558ad6f9c5d51519447451463</cites><orcidid>0000-0001-8497-9209 ; 0000-0002-5134-0975 ; 0000-0001-5371-6756 ; 0000-0002-8729-6005 ; 0000-0002-1697-6820 ; 0000-0002-8731-0540 ; 0000-0002-5435-0781 ; 0000-0002-0109-3312 ; 0000-0001-8465-5634 ; 0000-0002-7560-797X ; 0000-0002-7848-4688 ; 0000-0002-4594-6364 ; 0000-0002-0108-0255 ; 0000-0002-7522-5293</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhumu.24421$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhumu.24421$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids></links><search><creatorcontrib>Mroczek, Magdalena</creatorcontrib><creatorcontrib>Inashkina, Inna</creatorcontrib><creatorcontrib>Stavusis, Janis</creatorcontrib><creatorcontrib>Zayakin, Pawel</creatorcontrib><creatorcontrib>Khrunin, Andrey</creatorcontrib><creatorcontrib>Micule, Ieva</creatorcontrib><creatorcontrib>Kenina, Victorija</creatorcontrib><creatorcontrib>Zdanovica, Anna</creatorcontrib><creatorcontrib>Zídková, Jana</creatorcontrib><creatorcontrib>Fajkusová, Lenka</creatorcontrib><creatorcontrib>Limborska, Svetlana</creatorcontrib><creatorcontrib>Kooi, Anneke J.</creatorcontrib><creatorcontrib>Brusse, Esther</creatorcontrib><creatorcontrib>Leonardis, Lea</creatorcontrib><creatorcontrib>Maver, Ales</creatorcontrib><creatorcontrib>Pajusalu, Sander</creatorcontrib><creatorcontrib>Õunap, Katrin</creatorcontrib><creatorcontrib>Puusepp, Sanna</creatorcontrib><creatorcontrib>Dobosz, Paula</creatorcontrib><creatorcontrib>Sypniewski, Mateusz</creatorcontrib><creatorcontrib>Burnyte, Birute</creatorcontrib><creatorcontrib>Lace, Baiba</creatorcontrib><title>CAPN3 c.1746‐20C>G variant is hypomorphic for LGMD R1 calpain 3‐related</title><title>Human mutation</title><description>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.
Variant c.1746‐20C>G is a hypomorphic allele, associated with LGMD R1 calpain3‐related.</description><subject>Alternative splicing</subject><subject>Calpain</subject><subject>calpainopathy</subject><subject>CAPN3</subject><subject>hypomorphic variant</subject><subject>Isoforms</subject><subject>LGMD</subject><subject>LGMD R1 calpain 3‐related</subject><subject>Muscular dystrophy</subject><subject>Pathogenicity</subject><subject>Phenotypes</subject><subject>Reclassification</subject><issn>1059-7794</issn><issn>1098-1004</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp90M1Kw0AQB_AgCtbqxSdY8CJC6uxmP7IXoVRtxVZF7HnZbjY0JV_uNkpvPoLP6JOYGE8ePM0w_GYY_kFwimGEAcjluimaEaGU4L1ggEHGYTum-13PZCiEpIfBkfcbAIgZiwbB_WT89BAhM8KC8q-PTwKTqyl60y7T5RZlHq13dVVUrl5nBqWVQ_Pp4ho9Y2R0XuusRFG75GyutzY5Dg5SnXt78luHwfL25mUyC-eP07vJeB4aEjMcGpBJwuMIR5zYRDJqTKIlANerlZGUUAyci9QwFuuEp9KwhGGGJaWCMkx5NAzO-7u1q14b67eqyLyxea5LWzVeES4kl7EAaOnZH7qpGle23ykiQEILeacuemVc5b2zqapdVmi3UxhUl6vqclU_ubYY9_g9y-3uH6lmy8Wy3_kGa5x3dA</recordid><startdate>202210</startdate><enddate>202210</enddate><creator>Mroczek, Magdalena</creator><creator>Inashkina, Inna</creator><creator>Stavusis, Janis</creator><creator>Zayakin, Pawel</creator><creator>Khrunin, Andrey</creator><creator>Micule, Ieva</creator><creator>Kenina, Victorija</creator><creator>Zdanovica, Anna</creator><creator>Zídková, Jana</creator><creator>Fajkusová, Lenka</creator><creator>Limborska, Svetlana</creator><creator>Kooi, Anneke J.</creator><creator>Brusse, Esther</creator><creator>Leonardis, Lea</creator><creator>Maver, Ales</creator><creator>Pajusalu, Sander</creator><creator>Õunap, Katrin</creator><creator>Puusepp, Sanna</creator><creator>Dobosz, Paula</creator><creator>Sypniewski, Mateusz</creator><creator>Burnyte, Birute</creator><creator>Lace, Baiba</creator><general>Hindawi Limited</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-8497-9209</orcidid><orcidid>https://orcid.org/0000-0002-5134-0975</orcidid><orcidid>https://orcid.org/0000-0001-5371-6756</orcidid><orcidid>https://orcid.org/0000-0002-8729-6005</orcidid><orcidid>https://orcid.org/0000-0002-1697-6820</orcidid><orcidid>https://orcid.org/0000-0002-8731-0540</orcidid><orcidid>https://orcid.org/0000-0002-5435-0781</orcidid><orcidid>https://orcid.org/0000-0002-0109-3312</orcidid><orcidid>https://orcid.org/0000-0001-8465-5634</orcidid><orcidid>https://orcid.org/0000-0002-7560-797X</orcidid><orcidid>https://orcid.org/0000-0002-7848-4688</orcidid><orcidid>https://orcid.org/0000-0002-4594-6364</orcidid><orcidid>https://orcid.org/0000-0002-0108-0255</orcidid><orcidid>https://orcid.org/0000-0002-7522-5293</orcidid></search><sort><creationdate>202210</creationdate><title>CAPN3 c.1746‐20C>G variant is hypomorphic for LGMD R1 calpain 3‐related</title><author>Mroczek, Magdalena ; 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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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| source | Wiley Online Library - AutoHoldings Journals |
| subjects | Alternative splicing Calpain calpainopathy CAPN3 hypomorphic variant Isoforms LGMD LGMD R1 calpain 3‐related Muscular dystrophy Pathogenicity Phenotypes Reclassification |
| title | CAPN3 c.1746‐20C>G variant is hypomorphic for LGMD R1 calpain 3‐related |
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