{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T09:50:06Z","timestamp":1768902606819,"version":"3.49.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T00:00:00Z","timestamp":1704672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold><jats:italic>LMNA<\/jats:italic> splicing mutations occur in 9.1% of cases with cardiac involvement cases, but the phenotype and severity of disease they cause have not yet been systematically studied. The aim of this study was to understand the clinical and pathogenic characteristics of the <jats:italic>LMNA<\/jats:italic> splice-site mutation phenotype in patients with <jats:italic>LMNA<\/jats:italic>-related dilated cardiomyopathy (DCM) and sudden cardiac death (SCD).<\/jats:p><jats:p><jats:bold>Methods and Results:<\/jats:bold> First, we reported a novel family with <jats:italic>LMNA<\/jats:italic>-related DCM and SCD, and the clinical characteristics of all current patients with <jats:italic>LMNA<\/jats:italic> splicing mutations were further summarized through the ClinVar database. Seventeen families with a total of 134 individuals, containing a total of 15 <jats:italic>LMNA<\/jats:italic> splicing mutation sites, were enrolled. A total of 42 subjects (31.3%) had SCD. Compared without with the non-DCM group (<jats:italic>n<\/jats:italic> = 56), the patients within the DCM group (<jats:italic>n<\/jats:italic> = 78) presented a lower incidence of atrioventricular block (AVB) (<jats:italic>p<\/jats:italic> = 0.015) and a higher incidence rates of non-sustained ventricular tachycardia (<jats:italic>p<\/jats:italic> = 0.004),) and implantable cardioverter defibrillator (ICD) implantation (<jats:italic>p<\/jats:italic> = 0.005). Kaplan\u2012Meier survival analysis showed that the patients with pacemaker (PM) implantation had a significantly reduced the occurrence of SCD compared to patientswith those without PM implantation (log-rank <jats:italic>p<\/jats:italic> &amp;lt; 0.001), while there was no significant difference in ICD implantation between the two groups (log-rank <jats:italic>p<\/jats:italic> = 0.73). Second, we identified the family that we reported with a mutation in an LMNA c.513+1 G&amp;gt;A mutation in the reported family, and pathogenic prediction analysis showed that the mutation site was extremely harmful. Next, we conducted gene expression levels and cardiac pathological biopsy studies on the proband of this family. We found that the expression of normal <jats:italic>LMNA<\/jats:italic> mRNA from the proband was significantly downregulated in peripheral blood mononuclear cells than incompared with healthy individuals. Finally, we comprehensively summarized the pathological characteristics of <jats:italic>LMNA<\/jats:italic>-related DCM, including hypertrophy, atrophy, fibrosis, white blood cell infiltration, intercalated disc remodeling, and downregulation of desmin and connexin 43 (Cx43) expression.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> Above all, Cardiaccardiac involvement in patients with <jats:italic>LMNA<\/jats:italic> splice-site mutation presented with a high rate of SCD. Implanting a pacemaker significantly reduced the SCD rate in non-DCM patients with AVB. The pathogenic characterization was not only haveinvolved suppressed the expression of the healthy <jats:italic>LMNA<\/jats:italic> allele, but was also associated with abnormal expression and distribution of desmin and Cx43.<\/jats:p>","DOI":"10.3389\/fgene.2023.1291411","type":"journal-article","created":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T04:31:00Z","timestamp":1704688260000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Characterization of cardiac involvement in patients with LMNA splice-site mutation\u2013related dilated cardiomyopathy and sudden cardiac death"],"prefix":"10.3389","volume":"14","author":[{"given":"Xuebin","family":"Ling","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanjun","family":"Hou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingyu","family":"Jia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youling","family":"Lan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoping","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Jie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenling","family":"Wan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianfa","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junli","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiebiao","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e91","DOI":"10.1016\/j.jacc.2017.10.054","article-title":"2017 AHA\/ACC\/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of cardiology\/American heart association task force on clinical practice guidelines and the heart rhythm society","volume":"72","author":"Al-Khatib","year":"2018","journal-title":"J. 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