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

Calpain / genetics Humans Muscle Proteins / genetics Muscular Dystrophies, Limb-Girdle / genetics Mutation RNA Splicing

CAPN3 LGMD LGMD R1 calpain 3-related calpainopathy hypomorphic variant

Journal

Human mutation

ISSN: 1098-1004

Titre abrégé: Hum Mutat

Pays: United States

ID NLM: 9215429

Informations de publication

Date de publication:
10 2022

Historique:

revised: 07 05 2022

received: 10 12 2021

accepted: 02 06 2022

pubmed: 23 6 2022

medline: 9 9 2022

entrez: 22 6 2022

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1002/humu.24421 PMID: 35731190

pubmed: 35731190

doi: 10.1002/humu.24421

doi:

Substances chimiques

Muscle Proteins 0

CAPN3 protein, human EC 3.4.22.-

Calpain EC 3.4.22.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1347-1353

Informations de copyright

Références

Alrohaif, H., Pogoryelova, O., Al-Ajmi, A., Aljeryan, L. A., Alrashidi, N. H., Alefasi, S. A., Urtizberea, A., Lochmüller, H., & Bastaki, L. (2018). GNE myopathy in the bedouin population of Kuwait: Genetics, prevalence, and clinical description. Muscle and Nerve, 58, 700-707.

Angelini, C. F. M. (2005). Calpainopathy. Seattle: GeneReviews® [Internet]. University of Washington.

Balci, B., Aurino, S., Haliloglu, G., Talim, B., Erdem, S., Akcören, Z., Tan, E., Caglar, M., Richard, I., Nigro, V., Topaloglu, H., & Dincer, P. (2006). Calpain-3 mutations in Turkey. European Journal of Pediatrics, 165, 293-298.

Blázquez, L., Aiastui, A., Goicoechea, M., Martins de Araujo, M., Avril, A., Beley, C., García, L., Valcárcel, J., Fortes, P., & López de Munain, A. (2013). In vitro correction of a pseudoexon-generating deep intronic mutation in LGMD2A by antisense oligonucleotides and modified small nuclear RNAs. Human Mutation, 34, 1387-1395.

Cassa, C. A., Tong, M. Y., & Jordan, D. M. (2013). Large numbers of genetic variants considered to be pathogenic are common in asymptomatic individuals. Human Mutation, 34, 1216-1220.

Cerino, M., Campana-Salort, E., Salvi, A., Cintas, P., Renard, D., Juntas Morales, R., Tard, C., Leturcq, F., Stojkovic, T., Bonello-Palot, N., Gorokhova, S., Mortreux, J., Maues De Paula, A., Lévy, N., Pouget, J., Cossée, M., Bartoli, M., Krahn, M., & Attarian, S. (2020). Novel CAPN3 variant associated with an autosomal dominant calpainopathy. Neuropathology and Applied Neurobiology, 46, 564-578.

Chamova, T., Guergueltcheva, V., Gospodinova, M., Krause, S., Cirak, S., Kaprelyan, A., Angelova, L., Mihaylova, V., Bichev, S., Chandler, D., Naydenov, E., Grudkova, M., Djukmedzhiev, P., Voit, T., Pogoryelova, O., Lochmüller, H., Goebel, H. H., Bahlo, M., Kalaydjieva, L., & Tournev, I. (2015). GNE myopathy in Roma patients homozygous for the p.I618T founder mutation. Neuromuscular Disorders: NMD, 25, 713-718.

Dorobek, M., Ryniewicz, B., Kabzińska, D., Fidziańska, A., Styczyńska, M., & Hausmanowa-Petrusewicz, I. (2015). The frequency of c.550delA mutation of the CANP3 gene in the Polish LGMD2A population. Genetic Testing and Molecular Biomarkers, 19, 637-640.

Evilä, A., Palmio, J., Vihola, A., Savarese, M., Tasca, G., Penttilä, S., Lehtinen, S., Jonson, P. H., De Bleecker, J., Rainer P, Auer-Grumbach, M., Pouget, J., Salort-Campana, E., Vilchez, J. J., Muelas, N., Olive, M., Hackman, P., & Udd, B. (2017). Targeted next-generation sequencing reveals novel TTN mutations causing recessive distal titinopathy. Molecular Neurobiology, 54, 7212-7223.

Frosk, P., Bigio, M. R. D., Wrogemann, K., & Greenberg, C. R. (2005). Hutterite brothers both affected with two forms of limb girdle muscular dystrophy: LGMD2H and LGMD2I. European Journal of Human Genetics, 13, 978-982.

González-Mera, L., Ravenscroft, G., Cabrera-Serrano, M., Ermolova, N., Domínguez-González, C., Arteche-López, A., Soltanzadeh, P., Evesson, F., Navas, C., Mavillard, F., Clayton, J., Rodrigo, P., Servián-Morilla, E., Cooper, S. T., Waddell, L., Reardon, K., Corbett, A., Hernandez-Laín, A., Sanchez, A., … Olivé, M. (2021). Heterozygous CAPN3 missense variants causing autosomal-dominant calpainopathy in seven unrelated families. Neuropathology and Applied Neurobiology, 47, 283-296.

Gudmundsson, S., Singer-Berk, M., Watts, N. A., Phu, W., Goodrich, J. K., Solomonson, M., Rehm, H. L., MacArthur, D. G., & O'Donnell-Luria, A. (2022). Variant interpretation using population databases: Lessons from gnomAD. Human Mutation, 1-19.

Houge, G., Laner, A., Cirak, S., Leeuw, N. de, Scheffer, H., & Dunnen, J. T. den (2021). Stepwise ABC system for classification of any type of genetic variant. European Journal of Human Genetics, 30, 150-159.

Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alföldi, J., Wang, Q., Collins, R. L., Laricchia, K. M., Ganna, A., Birnbaum, D. P., Gauthier, L. D., Brand, H., Solomonson, M., Watts, N. A., Rhodes, D., Singer-Berk, M., England, E. M., Seaby, E. G., Kosmicki, J. A., … MacArthur, D. G. (2020). The mutational constraint spectrum quantified from variation in 141,456 humans. Nature, 581, 434-443.

Khrunin, A. V., Khokhrin, D. V., Filippova, I. N., Esko, T., Nelis, M., Bebyakova, N. A., Bolotova, N. L., Klovins, J., Nikitina-Zake, L., Rehnström, K., Ripatti, S., Schreiber, S., Franke, A., Macek, M., Krulišová, V., Lubinski, J., Metspalu, A., & Limborska, S. A. (2013). A genome-wide analysis of populations from European russia reveals a new pole of genetic diversity in Northern Europe. PLoS One, 8, e58552.

Krahn, M., Pécheux, C., Chapon, F., Béroud, C., Drouin-Garraud, V., Laforet, P., Romero, N., Penisson-Besnier, I., Bernard, R., Urtizberea, J., Leturcq, F., & Lévy, N. (2007). Transcriptional explorations of CAPN3 identify novel splicing mutations, a large-sized genomic deletion and evidence for messenger RNA decay. Clinical Genetics, 72, 582-592.

Kushniarevich, A., Utevska, O., Chuhryaeva, M., Agdzhoyan, A., Dibirova, K., Uktveryte, I., Möls, M., Mulahasanovic, L., Pshenichnov, A., Frolova, S., Shanko, A., Metspalu, E., Reidla, M., Tambets, K., Tamm, E., Koshel, S., Zaporozhchenko, V., Atramentova, L., Kučinskas, V., … Balanovsky, O. (2015). Genetic heritage of the Balto-Slavic speaking populations: a synthesis of autosomal, mitochondrial and Y-Chromosomal data. PLoS One, 10, e0135820.

Lasa-Elgarresta, J., Mosqueira-Martín, L., Naldaiz-Gastesi, N., Sáenz, A., López de Munain, A., & Vallejo-Illarramendi, A. (2019). Calcium mechanisms in Limb-Girdle muscular dystrophy with CAPN3 mutations. International Journal of Molecular Sciences, 20, 4548.

Macias A, Fichna JP, Topolewska M, Rȩdowicz MJ, Kaminska AM, Kostera-Pruszczyk A. (2021). Targeted next-generation sequencing reveals mutations in non-coding regions and potential regulatory sequences of Calpain-3 gene in Polish Limb-Girdle muscular dystrophy patients. Frontiers in Neuroscience, 15, 692482.

Nallamilli, B. R. R., Chakravorty, S., Kesari, A., Tanner, A., Ankala, A., Schneider, T., da Silva, C., Beadling, R., Alexander, J. J., Askree, S. H., Whitt, Z., Bean, L., Collins, C., Khadilkar, S., Gaitonde, P., Dastur, R., Wicklund, M., Mozaffar, T., Harms, M., … Hegde, M. (2018). Genetic landscape and novel disease mechanisms from a large <scp>LGMD</scp> cohort of 4656 patients. Annals of Clinical and Translational Neurology, 5, 1574-1587.

Nascimbeni, A. C., Fanin, M., Tasca, E., & Angelini, C. (2010). Transcriptional and translational effects of intronic CAPN3 gene mutations. Human Mutation, 31, E1658-E1669.

Raheem, O., Penttilä, S., Suominen, T., Kaakinen, M., Burge, J., Haworth, A., Sud, R., Schorge, S., Haapasalo, H., Sandell, S., Metsikkö, K., Hanna, M., & Udd, B. (2012). New immunohistochemical method for improved myotonia and chloride channel mutation diagnostics. Neurology, 79, 2194-2200.

Rekik, S., Sakka, S., Romdhan, S. B., Farhat, N., Baba Amer, Y., Lehkim, L., Authier, F. J., & Mhiri, C. (2019). Novel missense CAPN3 mutation responsible for Adult-Onset Limb Girdle muscular dystrophy with calves hypertrophy. Journal of Molecular Neuroscience, 69, 563-569.

Schutz, P. W., Scalco, R. S., Barresi, R., Houlden, H., Parton, M., & Holton, J. L. (2017). Calpainopathy with macrophage-rich, regional inflammatory infiltrates. Neuromuscular Disorders: NMD, 27, 738-741.

Sharkova, I. V., Bulakh, M. V., Bessonova, L. А., Shchagina, O. A., & Dadaly, E. L. (2021). A case of pseudodominant inheritance of limb-girdle muscular dystrophy caused by mutations in the CAPN3 gene. Ann Clin Exp Neurol, 15, 85-91.

Stehlíková, K., Zapletalová, E., Sedláčková, J., Hermanová, M., Vondráček, P., Maříková, T., Mazanec, R., Zámečník, J., Voháňka, S., Fajkus, J., & Fajkusová, L. (2007). Quantitative analysis of CAPN3 transcripts in LGMD2A patients: Involvement of nonsense-mediated mRNA decay. Neuromuscular Disorders: NMD, 17, 143-147.

Ten Dam, L., Frankhuizen, W. S., Linssen, W. H. J. P., Straathof, C. S., Niks, E. H., Faber, K., Fock, A., Kuks, J. B., Brusse E, de Coo, R., Voermans, N., Verrips, A., Hoogendijk, J. E., van der Pol, L., Westra, D., de Visser, M., van der Kooi, A. J., & Ginjaar, I. (2019). Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients. Clinical Genetics, 96, 126-133.

Vissing, J., Barresi, R., Witting, N., Van Ghelue, M., Gammelgaard, L., Bindoff, L. A., Straub, V., Lochmüller, H., Hudson, J., Wahl, C. M., Arnardottir, S., Dahlbom, K., Jonsrud, C., & Duno, M. (2016). A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy. Brain, 139, 2154-2163.

Vissing, J., Dahlqvist, J. R., Roudaut, C., Poupiot, J., Richard, I., Duno, M., & Krag, T. (2020). A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity. Human Mutation, 41, 1507-1513.