Garg, A., Speckman, R. A. & Bowcock, A. M. Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and -helical rod domains of the lamin A/C gene. Am. J. Med. 112, 549-555
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: Zhengmao Hu
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- "Mutations in LMNA have been identified as the cause of at least 12 different inherited disorders [10,11], known as laminopathies, which have significant phenotypic overlap . However, it remains unclear how different mutations in the LMNA gene cause such a variety of phenotypes. "
ABSTRACT: Introduction Hutchinson-Gilford progeria syndrome is a rare pediatric genetic syndrome with an incidence of one per eight million live births. The disorder is characterized by premature aging, generally leading to death due to myocardial infarction or stroke at approximately 13.4 years of age. The genetic diagnosis and special clinical manifestation in two Han Chinese siblings observed at our clinic for genetic counseling are described in this report. We screened the LMNA gene in these two siblings as well as in their unaffected parents. A homozygous mutation R527C was identified in the affected siblings, and both parents were heterozygous for this variant. Case presentation In case 1, the elder 10-year-old female sibling showed the classic physical and radiological changes of Hutchinson-Gilford progeria syndrome in addition to a considerable overlap with the phenotype of mandibuloacral dysplasia. In case 2, the younger male sibling had begun to show some early physical changes at age six months. Conclusion The phenotypic findings in the patients we describe here widen the clinical spectrum of Hutchinson-Gilford progeria syndrome symptoms, providing further recognition of the phenotypic range of LMNA-associated diseases.Journal of Medical Case Reports 03/2013; 7(1):63. DOI:10.1186/1752-1947-7-63
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- "This individual was found to have a severely dilated heart with reduced function. As with other LMNA mutations, cardiac conduction system disease was present with atrial fibrillation accompanied by a slow ventricular rate , , , . This mutation, LMNA E161K, has been previously reported in familial cardiomyopathy where it was shown to segregate with dilated cardiomyopathy and atrial fibrillation, and was not found in normal controls , . "
ABSTRACT: Lamins A and C, encoded by the LMNA gene, are filamentous proteins that form the core scaffold of the nuclear lamina. Dominant LMNA gene mutations cause multiple human diseases including cardiac and skeletal myopathies. The nuclear lamina is thought to regulate gene expression by its direct interaction with chromatin. LMNA gene mutations may mediate disease by disrupting normal gene expression. To investigate the hypothesis that mutant lamin A/C changes the lamina's ability to interact with chromatin, we studied gene misexpression resulting from the cardiomyopathic LMNA E161K mutation and correlated this with changes in chromosome positioning. We identified clusters of misexpressed genes and examined the nuclear positioning of two such genomic clusters, each harboring genes relevant to striated muscle disease including LMO7 and MBNL2. Both gene clusters were found to be more centrally positioned in LMNA-mutant nuclei. Additionally, these loci were less compacted. In LMNA mutant heart and fibroblasts, we found that chromosome 13 had a disproportionately high fraction of misexpressed genes. Using three-dimensional fluorescence in situ hybridization we found that the entire territory of chromosome 13 was displaced towards the center of the nucleus in LMNA mutant fibroblasts. Additional cardiomyopathic LMNA gene mutations were also shown to have abnormal positioning of chromosome 13, although in the opposite direction. These data support a model in which LMNA mutations perturb the intranuclear positioning and compaction of chromosomal domains and provide a mechanism by which gene expression may be altered.PLoS ONE 12/2010; 5(12):e14342. DOI:10.1371/journal.pone.0014342 · 3.23 Impact Factor
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- "The existence of a multi-system dystrophy syndrome has been described in two families presenting missense mutations in the amino-terminal head and a-helical rod domains of the lamin A/C gene; these mutations (R28W and R62G) had evidence of myocardial dystrophy, and mild muscular dystrophy in patients with FPLD (Garg et al., 2002). A detailed analysis of the known mutations in LMNA involved in laminopathies and their relationship with the clinical phenotype indicated that the clinical expression of the same mutation often varies in severity among members of the same family and that EDMD patients may show lipodystrophy (Brodsky et al., 2000). "
ABSTRACT: Just at the beginning of the millennium the neologism laminopathies has been introduced in the scientific vocabulary. An exponential increase of interest on the subject started concomitantly, so that a formerly quite neglected group of rare human diseases is now widely investigated. This review will cover the history of the identification of the molecular basis for fourteen (since now) hereditary diseases arising from defects in genes that encode nuclear envelope and nuclear lamina-associated proteins and will also consider the hypotheses that can account for the role of structural nuclear proteins in the pathogenesis of diseases affecting a wide spectrum of tissues.Journal of Cellular Physiology 05/2005; 203(2):319-27. DOI:10.1002/jcp.20217 · 3.87 Impact Factor