Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and alpha-helical rod domains of the lamin A/C gene
ABSTRACT Mutations in different domains of the LMNA (lamin A/C) gene encoding nuclear envelope proteins lamin A and lamin C cause familial partial lipodystrophy (Dunnigan variety), dilated cardiomyopathy, and autosomal dominant forms of Emery-Dreifuss and limb-girdle muscular dystrophies. The objective of this study was to evaluate LMNA variants in two families with familial partial lipodystrophy (Dunnigan variety) who also had cardiac conduction system defects and other manifestations related to cardiomyopathy. We performed mutational analysis of the lamin A/C gene in affected and unaffected subjects by deoxyribonucleic acid sequencing of the exons. Two novel missense mutations were identified in exon 1 of the lamin A/C gene. One mutation, R28W (CGG-->TGG), affected the amino-terminal head domain, and the other, R62G (CGC-->GGC), affected the alpha-helical rod domain. Affected subjects from both families had an increased prevalence of cardiac manifestations, such as atrioventricular conduction defects, atrial fibrillation, and heart failure due to ventricular dilatation, as well as pacemaker implantation. The proband from one of the families also had proximal muscle weakness. Novel genetic defects in the LMNA gene in two families with the Dunnigan variety of familial partial lipodystrophy, cardiac conduction system defects, and other manifestations related to cardiomyopathy suggest the occurrence of a multisystem dystrophy syndrome due to LMNA mutations.
SourceAvailable from: George M. Martin
Article: Molecular Basis of Progeroid Syndrome Molecular Basis of Progeroid Syndrome Molecular Basis of Progeroid Syndrome Molecular Basis of Progeroid Syndrome Molecular Basis of Progeroid Syndromes– s– s– s– s– the W the W the W the W the Werner and erner and erner and erner and erner and Hutchinson-Gilford Syndromes Hutchinson-Gilford Syndromes Hutchinson-Gilford Syndromes Hutchinson-Gilford Syndromes Hutchinson-Gilford Syndromes[Show abstract] [Hide abstract]
ABSTRACT: Segmental progeroid syndromes are members of a group of disorders in which affected individuals present various features suggestive of accelerated aging. The two best-known examples are the Werner syndrome (WS; "Progeria of the adult") and the Hutchinson-Gilford Progeria syndrome (HGPS; "Progeria of child-hood"). The gene responsible for WS, W R N, was identified in 1996 and encodes a multifunctional nuclear protein with exonuclease and helicase domains. WS patients and cells isolated from the WS patients show various genomic instability phenotypes, including an increased incidence of cancer. The WRN protein is thought to play a crucial role in optimizing the regulation of DNA repair processes. Recently, a novel recurrent mutation in the L M N A gene has been shown to be responsible for HGPS. L M N A encodes nuclear intermediate filaments, lamins A and C; mutant lamins are thought to result in nuclear fragility. There are at least six other disorders caused by L M N A mutations, most of which affect cells and tissues of mesenchymal origins, including atypical forms of WS. The pathophysiologies of these and certain other progeroid syndromes indicate an important role for DNA damage in the genesis of common age-related disorders.
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ABSTRACT: Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure (HF) and heart transplant. Mutations in 60 genes have been associated with DCM. Approximately 6% of all DCM cases are caused by mutations in the lamin A/C gene (LMNA). LMNA codes for type-V intermediate filaments that support the structure of the nuclear membrane and are involved in chromatin structure and gene expression. Most LMNA mutations result in striated muscle diseases while the rest affects the adipose tissue, peripheral nervous system, multiple tissues or lead to progeroid syndromes/overlapping syndromes. Patients with LMNA mutations exhibit a variety of cellular and physiological phenotypes. This paper explores the current phenotypes observed in LMNA-caused DCM, the results and implications of the cellular and animal models of DCM and the prevailing theories on the pathogenesis of laminopathies.Cardiology journal 05/2014; 21(4). DOI:10.5603/CJ.a2014.0037 · 1.22 Impact Factor
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ABSTRACT: The human KCNE1 protein forms the β-subunit of the IKs potassium channel and is important in the regulation of the atrial action potential duration. The purpose of this study was to investigate the association between the nonsynonymous 112G>A mutation of the KCNE1 gene and postcardiac surgery atrial fibrillation (AF). A cohort of patients scheduled for cardiac surgery was prospectively recruited. The genotype of 112G>A polymorphism was determined using polymerase chain reaction/restriction fragment analysis and confirmed with direct sequencing of the polymerase chain reaction product. In total, 509 patients were recruited in the study, of whom 203 (39.9%) had at least 1 qualifying episode of postoperative AF. An increased frequency of the G allele was observed in the postoperative AF group compared with the group without postoperative AF (0.628 vs 0.552, respectively, P = .016). The individual's relative risk of postoperative AF increased as the number of G alleles increased from 1.36 (95% CI 0.89-2.08) for G allele heterozygotes to 1.62 (95% CI 1.08-2.43) for G allele homozygotes (P = .04 for trend). The multivariate analysis revealed the abnormal ejection fraction (odds ratio [OR] 1.585, 95% CI 1.076-2.331, P = .020), age (OR 1.043, 95% CI 1.022-1.064, P < .001), type of surgery (aortic valve replacement) (OR 1.869, 95% CI 1.094-3.194, P = .022), and the 112G>A genotype (OR 1.401 [in additive model], 95% CI 1.052-1.865, P = .021) to be independent predictors of postoperative AF. This study confirmed the association of the 112G>A polymorphism and postoperative AF in a cohort of patients undergoing cardiac surgery.American heart journal 02/2014; 167(2):274-280.e1. DOI:10.1016/j.ahj.2013.09.020 · 4.56 Impact Factor