{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T12:13:42Z","timestamp":1781180022192,"version":"3.54.1"},"reference-count":37,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,25]],"date-time":"2025-01-25T00:00:00Z","timestamp":1737763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Laminopathies are a broad spectrum of hereditary diseases caused by pathogenic variants of the LMNA gene. Such phenotypic diversity is explained by the function of intermediate filaments encoded by the LMNA gene. We examined a family with an overlapping phenotype of cardiac arrhythmia, cardiomyopathy, limb\u2013girdle muscular dystrophy, and partial lipodystrophy. The cause of the disorder was a novel LMNA(NM_170707.4):c.1488+2T&gt;C variant. The analysis of mRNA extracted from the probands\u2019 blood showed a multitude of alternative splicing products, which was the cause of the complex phenotype in affected family members. Aside from that, we used minigene constructs to analyze the c.1488+2T&gt;C variant, as well as other previously described variants affecting the same donor splice site in intron 8 (c.1488+1G&gt;A, c.1488+5G&gt;C, c.1488+5G&gt;A). We demonstrated that these variants result in multiple splicing events, each producing splicing products with varying prevalence. Our experiments suggest that the variety of alternative transcripts contributes to complex phenotypes, while the quantitative ratio of these transcripts influences the varying severity of the disease.<\/jats:p>","DOI":"10.3390\/ijms26031015","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T03:54:27Z","timestamp":1737950067000},"page":"1015","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Basis of Diversity in Laminopathy Phenotypes Caused by Variants in the Intron 8 Donor Splice Site of the LMNA Gene"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4905-1303","authenticated-orcid":false,"given":"Olga","family":"Shchagina","sequence":"first","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1716-5963","authenticated-orcid":false,"given":"Leisan","family":"Gilazova","sequence":"additional","affiliation":[{"name":"Republic of Tatarstan Ministry of Healthcare Autonomous Public Healthcare, Institution Republic Clinical Hospital, 420064 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5979-0727","authenticated-orcid":false,"given":"Alexandra","family":"Filatova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zulfiia","family":"Vafina","sequence":"additional","affiliation":[{"name":"Republic of Tatarstan Ministry of Healthcare Autonomous Public Healthcare, Institution Republic Clinical Hospital, 420064 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7023-7378","authenticated-orcid":false,"given":"Aysylu","family":"Murtazina","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7554-3670","authenticated-orcid":false,"given":"Polina","family":"Chigvintceva","sequence":"additional","affiliation":[{"name":"Republic of Tatarstan Ministry of Healthcare Autonomous Public Healthcare, Institution Republic Clinical Hospital, 420064 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Kudryashova","sequence":"additional","affiliation":[{"name":"Republic of Tatarstan Ministry of Healthcare Autonomous Public Healthcare, Institution Republic Clinical Hospital, 420064 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksander","family":"Polyakov","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Kutsev","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8674-7230","authenticated-orcid":false,"given":"Maria","family":"Bulakh","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7293-3438","authenticated-orcid":false,"given":"Mikhail","family":"Skoblov","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.semcdb.2014.01.001","article-title":"Striated Muscle Laminopathies","volume":"29","author":"Azibani","year":"2014","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/cge.13455","article-title":"Complex Effects of Laminopathy Mutations on Nuclear Structure and Function","volume":"95","author":"Ho","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1038\/ng1852","article-title":"Characterization of the Drosophila Melanogaster Genome at the Nuclear Lamina","volume":"38","author":"Pickersgill","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.cell.2017.04.022","article-title":"Lamina-Associated Domains: Links with Chromosome Architecture, Heterochromatin and Gene Repression","volume":"169","author":"Belmont","year":"2017","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1016\/j.yexcr.2007.03.028","article-title":"\u201cLaminopathies\u201d: A Wide Spectrum of Human Diseases","volume":"313","author":"Worman","year":"2007","journal-title":"Exp. Cell Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1083\/jcb.200509124","article-title":"Coupling of the Nucleus and Cytoplasm: Role of the LINC Complex","volume":"172","author":"Crisp","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1093\/hmg\/ddh295","article-title":"Decreased Mechanical Stiffness in LMNA\u2212\/\u2212 Cells Is Caused by Defective Nucleo-Cytoskeletal Integrity: Implications for the Development of Laminopathies","volume":"13","author":"Broers","year":"2004","journal-title":"Human Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1002\/jcb.22992","article-title":"Laminopathies and Lamin-Associated Signaling Pathways","volume":"112","author":"Maraldi","year":"2011","journal-title":"J. Cell Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1093\/hmg\/ddh265","article-title":"Lamin A and ZMPSTE24 (FACE-1) Defects Cause Nuclear Disorganization and Identify Restrictive Dermopathy as a Lethal Neonatal Laminopathy","volume":"13","author":"Navarro","year":"2004","journal-title":"Human Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1007\/s00439-020-02199-3","article-title":"The Human Gene Mutation Database (HGMD\u00ae): Optimizing Its Use in a Clinical Diagnostic or Research Setting","volume":"139","author":"Stenson","year":"2020","journal-title":"Human Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1136\/jmedgenet-2016-104295","article-title":"A Novel Somatic Mutation Achieves Partial Rescue in a Child with Hutchinson-Gilford Progeria Syndrome","volume":"54","author":"Bar","year":"2017","journal-title":"J. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.gene.2014.05.042","article-title":"Pro4Arg Mutation in LMNA Gene: A New Atypical Progeria Phenotype without Metabolism Abnormalities","volume":"546","author":"Guo","year":"2014","journal-title":"Gene"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3002","DOI":"10.1002\/ajmg.a.34336","article-title":"Coronary Artery Disease in a Werner Syndrome-like Form of Progeria Characterized by Low Levels of Progerin, a Splice Variant of Lamin A","volume":"155","author":"Hisama","year":"2011","journal-title":"Am. J. Med. Genet. Pt. A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1111\/j.1399-0004.2004.00315.x","article-title":"Hutchinson\u2013Gilford Progeria Syndrome","volume":"66","author":"Pollex","year":"2004","journal-title":"Clin. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1172\/JCI37679","article-title":"Laminopathies and the Long Strange Trip from Basic Cell Biology to Therapy","volume":"119","author":"Worman","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nature01629","article-title":"Recurrent de Novo Point Mutations in Lamin A Cause Hutchinson\u2013Gilford Progeria Syndrome","volume":"423","author":"Eriksson","year":"2003","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1136\/jmg.2003.014688","article-title":"LMNA Mutation in a 45 Year Old Japanese Subject with Hutchinson-Gilford Progeria Syndrome","volume":"41","author":"Fukuchi","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1002\/humu.20536","article-title":"Increased Progerin Expression Associated with Unusual LMNA Mutations Causes Severe Progeroid Syndromes","volume":"28","author":"Moulson","year":"2007","journal-title":"Human Mutat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.nmd.2017.06.008","article-title":"Congenital Muscular Dystrophies in the UK Population: Clinical and Molecular Spectrum of a Large Cohort Diagnosed over a 12-Year Period","volume":"27","author":"Sframeli","year":"2017","journal-title":"Neuromuscul. Disord."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1210\/jc.2005-2746","article-title":"A LMNA Splicing Mutation in Two Sisters with Severe Dunnigan-Type Familial Partial Lipodystrophy Type 2","volume":"91","author":"Morel","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17381","DOI":"10.1074\/jbc.C200038200","article-title":"Structure of the Globular Tail of Nuclear Lamin*","volume":"277","author":"Werner","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1002\/humu.23821","article-title":"First Estimate of the Scale of Canonical 5\u2032 Splice Site GT>GC Variants Capable of Generating Wild-type Transcripts","volume":"40","author":"Lin","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1194\/jlr.R700004-JLR200","article-title":"Thematic Review Series: Adipocyte Biology. Lipodystrophies: Windows on Adipose Biology and Metabolism","volume":"48","author":"Hegele","year":"2007","journal-title":"J. Lipid Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/gim.2013.73","article-title":"ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing","volume":"15","author":"Green","year":"2013","journal-title":"Genet. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: The Human Genomic Variant Search Engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1007\/s12471-019-1250-5","article-title":"Large Next-Generation Sequencing Gene Panels in Genetic Heart Disease: Yield of Pathogenic Variants and Variants of Unknown Significance","volume":"27","author":"Mook","year":"2019","journal-title":"Neth. Heart J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1016\/j.jacc.2016.08.058","article-title":"Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A\/C Mutation Carriers","volume":"68","author":"Kumar","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"fcab075","DOI":"10.1093\/braincomms\/fcab075","article-title":"International Retrospective Natural History Study of LMNA-Related Congenital Muscular Dystrophy","volume":"3","author":"Yun","year":"2021","journal-title":"Brain Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.yjmcc.2007.11.008","article-title":"Lamin A\/C Haploinsufficiency Causes Dilated Cardiomyopathy and Apoptosis-Triggered Cardiac Conduction System Disease","volume":"44","author":"Wolf","year":"2008","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1002\/humu.23747","article-title":"Noncompaction Cardiomyopathy Is Caused by a Novel In-frame Desmin (DES) Deletion Mutation within the 1A Coiled-coil Rod Segment Leading to a Severe Filament Assembly Defect","volume":"40","author":"Marakhonov","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Brodehl, A., Hain, C., Flottmann, F., Ratnavadivel, S., Gaertner, A., Klauke, B., Kalinowski, J., K\u00f6rperich, H., Gummert, J., and Paluszkiewicz, L. (2021). The Desmin Mutation DES-c.735G>C Causes Severe Restrictive Cardiomyopathy by Inducing In-Frame Skipping of Exon-3. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101400"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1002\/humu.21361","article-title":"Novel LMNA Mutations in Patients with Emery-Dreifuss Muscular Dystrophy and Functional Characterization of Four LMNA Mutations","volume":"32","author":"Scharner","year":"2011","journal-title":"Human Mutat."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3068","DOI":"10.1210\/jc.2018-02787","article-title":"Efficacy of Metreleptin Treatment in Familial Partial Lipodystrophy Due to PPARG vs LMNA Pathogenic Variants","volume":"104","author":"Sekizkardes","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Paulsen, J., Sekelja, M., Oldenburg, A.R., Barateau, A., Briand, N., Delbarre, E., Shah, A., S\u00f8rensen, A.L., Vigouroux, C., and Buendia, B. (2017). Chrom3D: Three-Dimensional Genome Modeling from Hi-C and Nuclear Lamin-Genome Contacts. Genome Biol., 18.","DOI":"10.1186\/s13059-016-1146-2"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/s41431-018-0288-y","article-title":"Functional Reassessment of PAX6 Single Nucleotide Variants by in Vitro Splicing Assay","volume":"27","author":"Filatova","year":"2019","journal-title":"Eur. J. Human Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/978-1-4939-6472-7_26","article-title":"An In Vitro Single-Primer Site-Directed Mutagenesis Method for Use in Biotechnology","volume":"Volume 1498","author":"Reeves","year":"2017","journal-title":"Vitro Mutagenesis"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"pdb.prot3872","DOI":"10.1101\/pdb.prot3872","article-title":"Calcium-Phosphate-Mediated Transfection of Cells with High-Molecular-Weight Genomic DNA","volume":"2006","author":"Sambrook","year":"2006","journal-title":"Cold Spring Harb. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/3\/1015\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:35:55Z","timestamp":1759919755000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/3\/1015"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,25]]},"references-count":37,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["ijms26031015"],"URL":"https:\/\/doi.org\/10.3390\/ijms26031015","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,25]]}}}