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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LGMD1B is an autosomal dominantly inherited, slowly progressive limb girdle muscular dystrophy, with age-related atrioventricular cardiac conduction disturbances and the absence of early contractures. The disease has been linked to chromosome 1q11-q21. Within this locus another muscular dystrophy, the autosomal dominant form of Emery-Dreifuss muscular dystrophy (AD-EDMD) has recently been mapped and the corresponding gene identified. AD-ADMD is characterized by early contractures of elbows and Achilles tendons and a humero-peroneal distribution of weakness combined with a cardiomyopathy with conduction defects. The disease gene of AD-EDMD is LMNA which encodes lamins A/C, two proteins of the nuclear envelope. In order to identify whether or not LGMD1B and AD-EDMD are allelic disorders, we carried out a search for mutations in the LMNA gene in patients with LGMD1B. For this, PCR/SSCP/sequencing screening was carried out for the 12 exons of LMNA on DNA samples of individuals from three LGMD1B families that were linked to chromo-some 1q11-q21. Mutations were identified in all three LGMD1B families: a missense mutation, a deletion of a codon and a splice donor site mutation, respectively. The three mutations were identified in all affected members of the corresponding families and were absent in 100 unrelated control subjects. The present identification of mutations in the LMNA gene in LGMD1B demonstrates that LGMD1B and AD-EDMD are allelic disorders. Further analysis of phenotype-genotype relationship will help to clarify the variability of the phenotype observed in these two muscular dystrophies.
Hum Mol Genet 2000 May 22
PMID:Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). 1081 26

The X-linked form of Emery-Dreifuss muscular dystrophy (X-EDMD) is caused by absence, or greatly reduced amounts, of the inner nuclear-membrane protein, emerin. The autosomal dominant form (AD-EDMD) is caused by missense mutations in lamins A and C, two components of the nuclear lamina that interact directly with emerin. Lamin A/C mutations also cause one form of dilated cardiomyopathy (CMD1A) and one form of limb-girdle muscular dystrophy (LGMD1B), both of which have clinical features in common with EDMD, as well as a rare, unrelated form of lipodystrophy (FPLD). Evidence is now emerging that defective assembly of the nuclear lamina is a feature of all these diseases, although not necessarily the direct cause. Why only heart and skeletal muscle, and possibly connective tissue, are affected in EDMD and why expression of the disease is so extremely variable between individuals remains to be explained.
Trends Mol Med 2001 Dec
PMID:The role of the nuclear envelope in Emery-Dreifuss muscular dystrophy. 1173 21

The nuclear lamins polymerize to form the nuclear lamina, a fibrous structure found on the inner face of the nuclear membrane. The lamins also appear to form structures within the nucleoplasm. These various lamin structures help to establish and maintain the shape and strength of the interphase nucleus, but recent work also suggests that the lamins have a role in nuclear processes such as DNA replication. Furthermore, mutations in the human lamin A/C gene have recently been linked to several diseases, including Emery-Dreifuss muscular dystrophy. This review discusses the nature of these mutations and the possible effects of lamin mutations on nuclear function.
Cell Mol Life Sci 2001 Nov
PMID:The structure and function of nuclear lamins: implications for disease. 1176 74

The gene encoding nuclear lamins A and C is mutated in at least three inherited disorders. Two of these, Emery-Dreifuss muscular dystrophy (EDMD-AD) and a form of dilated cardiomyopathy (CMD1A), involve muscle defects, and the other, familial partial lipodystrophy (FPLD), involves loss of subcutaneous adipose tissue. Mutations causing FPLD, in contrast to those causing muscle disorders, are tightly clustered within the C-terminal domain of lamin A/C. We investigated the expression and subcellular localization of FPLD lamin A mutants and found no abnormalities. We therefore set out to identify proteins interacting with the C-terminal domain of lamin A by screening a mouse 3T3-L1 adipocyte library in a yeast two-hybrid interaction screen. Using this approach, the adipocyte differentiation factor, sterol response element binding protein 1 (SREBP1) was identified as a novel lamin A interactor. In vitro glutathione S-transferase pull-down and in vivo co-immunoprecipitation studies confirmed an interaction between lamin A and both SREBP1a and 1c. A binding site for lamin A was identified in the N-terminal transcription factor domain of SREBP1, between residues 227 and 487. The binding of lamin A to SREBP1 was noticeably reduced by FPLD mutations. Interestingly, one EDMD-AD mutation also interfered with the interaction between lamin A and SREBP1. Whilst the physiological relevance of this interaction has yet to be elucidated, these data raise the intriguing possibility that fat loss seen in laminopathies may be caused, at least in part, by reduced binding of the adipocyte differentiation factor SREBP1 to lamin A.
Hum Mol Genet 2002 Apr 01
PMID:A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies. 1192 49

Autosomal dominantly inherited missense mutations in lamins A and C cause several tissue-specific diseases, including Emery-Dreifuss muscular dystrophy (EDMD) and Dunnigan-type familial partial lipodystrophy (FPLD). Here we analyze myoblast-to-myotube differentiation in C2C12 clones overexpressing lamin A mutated at arginine 453 (R453W), one of the most frequent mutations in EDMD. In contrast with clones expressing wild-type lamin A, these clones differentiate poorly or not at all, do not exit the cell cycle properly, and are extensively committed to apoptosis. These disorders are correlated with low levels of expression of transcription factor myogenin and with the persistence of a large pool of hyperphosphorylated retinoblastoma protein. Since clones mutated at arginine 482 (a site responsible for FPLD) differentiate normally, we conclude that C2C12 clones expressing R453W-mutated lamin A represent a good cellular model to study the pathophysiology of EDMD. Our hypothesis is that lamin A mutated at arginine 453 fails to build a functional scaffold and/or to maintain the chromatin compartmentation required for differentiation of myoblasts into myocytes.
Mol Cell Biol 2004 Feb
PMID:Expression of a mutant lamin A that causes Emery-Dreifuss muscular dystrophy inhibits in vitro differentiation of C2C12 myoblasts. 1474 66

Laminopathies are a group of disorders caused by mutations in the LMNA gene encoding A-type lamins, components of the nuclear lamina. Three of these disorders affect specifically the skeletal and/or cardiac muscles, and their pathogenic mechanisms are still unknown. We chose the LMNA H222P missense mutation identified in a family with autosomal dominant Emery-Dreifuss muscular dystrophy, one of the striated muscle-specific laminopathies, to create a faithful mouse model of this type of laminopathy. The mutant mice exhibit overtly normal embryonic development and sexual maturity. At adulthood, male homozygous mice display reduced locomotion activity with abnormal stiff walking posture and all of them die by 9 months of age. As for cardiac phenotype, they develop chamber dilation and hypokinesia with conduction defects. These abnormal skeletal and cardiac features were also observed in the female homozygous mice but with a later-onset than in males. Histopathological analysis of the mice revealed muscle degeneration with fibrosis associated with dislocation of heterochromatin and activation of Smad signalling in heart and skeletal muscles. These results demonstrate that LmnaH222P/H222P mice represent a good model for studying laminopathies affecting striated muscles as they develop a dystrophic condition of both skeletal and cardiac muscles similar to the human diseases.
Hum Mol Genet 2005 Jan 01
PMID:Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies. 1554 45

Many nuclear proteins form lamin-dependent complexes, including LEM-domain proteins, nesprins and SUN-domain proteins. These complexes have roles in chromatin organization, gene regulation and signal transduction. Some link the nucleoskeleton to cytoskeletal structures, ensuring that the nucleus and centrosome assume appropriate intracellular positions. These complexes provide new insights into cell architecture, as well as a foundation for the understanding of the molecular mechanisms that underlie the human laminopathies - clinical disorders that range from Emery-Dreifuss muscular dystrophy to the accelerated ageing seen in Hutchinson-Gilford progeria syndrome.
Nat Rev Mol Cell Biol 2005 Jan
PMID:The nuclear lamina comes of age. 1568 64

Barrier-to-autointegration factor (BAF) is a conserved 10-kDa chromatin protein essential in proliferating cells. BAF dimers bind double-stranded DNA, histone H3, histone H1.1, lamin A, and transcription regulators, plus emerin and other LEM-domain nuclear proteins. Two-dimensional gel analysis showed that endogenous human and Xenopus BAF are posttranslationally modified by phosphorylation and potentially other modifications and that they are hyperphosphorylated during mitosis. The invariant Ser-4 residue on BAF is a major site of phosphorylation during both interphase and mitosis. In HeLa cells that overexpressed the phosphomimetic BAF missense mutant S4E, but not S4A, emerin mislocalized from the nuclear envelope, suggesting Ser-4-nonphosphorylated BAF normally promotes emerin localization at the nuclear envelope. Supporting this model, wild-type BAF but not mutant S4E enhanced emerin binding to lamin A in vitro. Thus, Ser-4-unphosphorylated BAF has a positive role in localizing emerin; this role may be disease relevant because loss or mislocalization of emerin causes Emery-Dreifuss muscular dystrophy. Our findings further suggest Ser-4 phosphorylation inhibits BAF binding to emerin and lamin A, and thereby weakens emerin-lamin interactions during both mitosis and interphase.
Mol Biol Cell 2006 Mar
PMID:Barrier-to-autointegration factor phosphorylation on Ser-4 regulates emerin binding to lamin A in vitro and emerin localization in vivo. 1637 12

Emery-Dreifuss muscular dystrophy (EDMD1) is caused by mutations in either the X-linked gene emerin (EMD) or the autosomal lamin A/C (LMNA) gene. Here, we describe the derivation of mice lacking emerin in an attempt to derive a mouse model for EDMD1. Although mice lacking emerin show no overt pathology, muscle regeneration in these mice revealed defects. A bioinformatic array analysis of regenerating Emd null muscle revealed abnormalities in cell-cycle parameters and delayed myogenic differentiation, which were associated with perturbations to transcriptional pathways regulated by the retinoblastoma (Rb1) and MyoD genes. Temporal activation of MyoD transcriptional targets was significantly delayed, whereas targets of the Rb1/E2F transcriptional repressor complex remained inappropriately active. The inappropriate modulation of Rb1/MyoD transcriptional targets was associated with up-regulation of Rb1, MyoD and their co-activators/repressors transcripts, suggesting a compensatory effort to overcome a molecular block to differentiation at the myoblast/myotube transition during regeneration. This compensation appeared to be effective for MyoD transcriptional targets, although was less effective for Rb1 targets. Analysis of Rb1 phosphorylation states showed prolonged hyper-phosphorylation at key developmental stages in Emd null myogenic cells, both in vivo and in vitro. We also analyzed the same pathways in Lmna null muscle, which shows extensive dystrophy. Surprisingly, Lmna null muscle did not show the same perturbations to Rb- and MyoD-dependent pathways. We did observe increased transcriptional expression of Lap2alpha and delayed expression of Rb1, which may regulate alternative transcriptional pathways in the Lmna null myoblasts. We suggest that the dominant LMNA mutations seen in many clinically disparate laminopathies may similarly alter Rb function, with regard to either the timing of exit from the cell cycle or terminal differentiation programs or both.
Hum Mol Genet 2006 Feb 15
PMID:Loss of emerin at the nuclear envelope disrupts the Rb1/E2F and MyoD pathways during muscle regeneration. 1640 4

Mutations in the LMNA gene encoding A-type lamins cause several diseases, including Emery-Dreifuss muscular dystrophy and Dunnigan-type familial partial lipodystrophy (FPLD). We analyzed differentiation of 3T3-L1 preadipocytes to adipocytes in cells overexpressing wild-type lamin A as well as lamin A with amino acid substitutions at position 482 that cause FPLD. We also examined adipogenic conversion of mouse embryonic fibroblasts lacking A-type lamins. Overexpression of both wild-type and mutant lamin A inhibited lipid accumulation, triglyceride synthesis and expression of adipogenic markers. This was associated with inhibition of expression of peroxisome-proliferator-activated receptor gamma 2 (PPARgamma2) and Glut4. In contrast, embryonic fibroblasts lacking A-type lamins accumulated more intracellular lipid and exhibited elevated de novo triglyceride synthesis compared with wild-type fibroblasts. They also had increased basal phosphorylation of AKT1, a mediator of insulin signaling. We conclude that A-type lamins act as inhibitors of adipocyte differentiation, possibly by affecting PPARgamma2 and insulin signaling.
Hum Mol Genet 2006 Feb 15
PMID:Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy. 1641 42


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