A rare cause of familial atrioventricular block with a novel LMNA mutation (p. Ala502Val)

Mutation in LMNA accounts for 10% of Dilated Cardiomyopathy (DCM). It is characterised by progressive conduction system disease, arrhythmia and systolic impairment, lamin A/C heart disease is the most malignant gene common in DCMs especially in man. It is likely to be an under-recognised cause of this cardiomyopathy. In certain clinical scenarios, particularly familial DCM with early conduction disease, the probability of finding an LMNA mutation may be quite high.

Timing of pacemaker and ICD implantation in LMNA mutation carriers

AimsLMNA-cardiomyopathy is often associated with pathology in the cardiac conduction system necessitating device implantations. The aim was to study the timing and types of device implantations and need for re-implantations in LMNA mutation carriers.MethodsWe studied the hospital records of 60 LMNA mutation carriers concerning device implantations and re-implantations and their indications. Data were collected until April 2019.ResultsThe median follow-up time from the first ECG recording to the last clinical follow-up, transplantation, or death was 7.7 (IQR=9.1) years. Altogether 61.7% (n=37) of the LMNA mutation carriers received a pacemaker or an implantable cardioverter defibrillator (ICD), and of them 27.0% (n=10) needed a device upgrade. Notably, in some patients the upgrade took place very soon after the first implantation. The first device was implanted at an average age of 47.9 years (SD=9.5), whereas the upgrade took place at an average age of 50.3 years (SD=8.1). Most upgrades were ICD implantations. Male patients underwent device upgrade more often and at a younger age than women. By the end of follow-up, 35.0% (n=21) of the patients fulfilled echocardiographic criteria for dilated cardiomyopathy, and 90.5% of them (n=19) needed pacemaker implantation.ConclusionMost LMNA mutation carriers underwent pacemaker implantation in this study. Due to the progressive nature of LMNA-cardiomyopathy, device upgrades are quite common. An ICD should be considered when the initial device implantation is planned in an LMNA mutation carrier.

Integrated analysis reveals the alterations that LMNA interacts with euchromatin in LMNA mutation-associated dilated cardiomyopathy

Background Dilated cardiomyopathy (DCM) is a serious cardiac heterogeneous pathological disease, which may be caused by mutations in the LMNA gene. Lamins interact with not only lamina-associated domains (LADs) but also euchromatin by alone or associates with the lamina-associated polypeptide 2 alpha (LAP2α). Numerous studies have documented that LMNA regulates gene expression by interacting with LADs in heterochromatin. However, the role of LMNA in regulating euchromatin in DCM is poorly understood. Here, we determine the differential binding genes on euchromatin in DCM induced by LMNA mutation by performing an integrated analysis of bioinformatics and explore the possible molecular pathogenesis mechanism. Results Six hundred twenty-three and 4484 differential binding genes were identified by ChIP-seq technology. The ChIP-seq analysis results and matched RNA-Seq transcriptome data were integrated to further validate the differential binding genes of ChIP-seq. Five and 60 candidate genes involved in a series of downstream analysis were identified. Finally, 4 key genes (CREBBP, PPP2R2B, BMP4, and BMP7) were harvested, and these genes may regulate LMNA mutation-induced DCM through WNT/β-catenin or TGFβ-BMP pathways. Conclusions We identified four key genes that may serve as potential biomarkers and novel therapeutic targets. Our study also illuminates the possible molecular pathogenesis mechanism that the abnormal binding between LMNA or LAP2α-lamin A/C complexes and euchromatin DNA in LMNA mutations, which may cause DCM through the changes of CREBBP, PPP2R2B, BMP4, BMP7 expressions, and the dysregulation of WNT/β-catenin or TGFβ-BMP pathways, providing valuable insights to improve the occurrence and development of DCM. Graphic abstract

Ryanodine receptor remodeling in cardiomyopathy and muscular dystrophy caused by lamin A/C gene mutation

Mutations in the lamin A/C gene (LMNA), which encodes A-type lamins, cause several diseases called laminopathies, the most common of which is dilated cardiomyopathy with muscular dystrophy. The role of Ca2+ regulation in these diseases remain poorly understood. We now show biochemical remodeling of the ryanodine receptor (RyR)/intracellular Ca2+ release channel in heart samples from human subjects with LMNA mutations, including protein kinase A-catalyzed phosphorylation, oxidation and depletion of the stabilizing subunit calstabin. In the LmnaH222P/H222P murine model of Emery-Dreifuss muscular dystrophy caused by LMNA mutation, we demonstrate an age-dependent biochemical remodeling of RyR2 in heart and RyR1 in skeletal muscle. This RyR remodeling is associated with heart and skeletal muscle dysfunction. Defective heart and muscle function are ameliorated by treatment with a novel Rycal small molecule drug (S107) that fixes ‘leaky’ RyRs. SMAD3 phosphorylation is increased in hearts and diaphragms of LmnaH222P/H222P mice, which enhances NADPH oxidase binding to RyR channels, contributing to their oxidation. There is also increased generalized protein oxidation, increased calcium/calmodulin-dependent protein kinase II-catalyzed phosphorylation of RyRs and increased protein kinase A activity in these tissues. Our data show that RyR remodeling plays a role in cardiomyopathy and skeletal muscle dysfunction caused by LMNA mutation and identify these Ca2+ channels as a potential therapeutic target.

Familial dilated cardiomyopathy with a novel LMNA mutation (p.R429C): a case report

LMNA mutations cause a variety of inherited diseases referred to as laminopathies which are associated with a wide spectrum of disease phenotypes, ranging from skeletal muscle disease, pre-mature ageing, metabolic disorders, and cardiac abnormalities. We present a case of a 14-year-old boy with dilated cardiomyopathy induced by the LMNA mutation (p. R429C) and described its electrocardiogram and imaging features.

Atypical Progeroid Syndrome and Partial Lipodystrophy Due to LMNA Gene p.R349W Mutation

Atypical progeroid syndrome (APS) comprises heterogeneous disorders characterized by variable degrees of fat loss, metabolic alterations, and comorbidities that affect skeleton, muscles, and/or the heart. We describe 3 patients that were referred to our center for the suspicion of lipodystrophy. They had precocious aging traits such as short stature, mandibular hypoplasia, beaked nose, and partial alopecia manifesting around 10 to 15 years of age recurrently associated with: (1) partial lipodystrophy; (2) proteinuric nephropathy; (3) heart disease (rhythm disorders, valvular abnormalities, and cardiomyopathy); and (4) sensorineural hearing impairment. In all patients, genetic testing revealed a missense heterozygous lamin A/C gene (LMNA) mutation c.1045 C > T (p.Arg349Trp). Ten patients with LMNA p.R349W mutation have been reported so far, all presenting with similar features, which represent the key pathological hallmarks of this subtype of APS. The associated kidney and cardiac complications occurring in the natural history of the disease may reduce life expectancy. Therefore, in these patients a careful and periodic cardiac and kidney function evaluation is required.