Sequencing of the Reannotated LMNB2 Gene Reveals Novel Mutations in Patients with Acquired Partial Lipodystrophy

Hegele, Robert A.; Cao, Henian; Liu, Dora M.; Costain, Gary; Charlton-Menys, Valentine; Rodger, N. W.; Durrington, Paul N.

doi:10.1086/505885

Cited by 180 publications

(119 citation statements)

References 26 publications

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“…Duplication of LMNB1, which leads to an increase in lamin B1 expression, causes adult-onset autosomal-dominant leukodystrophy, a slowly progressive neurological disorder characterized by symmetrical widespread myelin loss in the central nervous system [63]. Mutations in LMNB2 have been reported to lead to susceptibility to acquired partial lipodystrophy [64]. In mice, homozygous Lmnb1 and Lmnb2 deletions both cause neonatal lethality, with Lmnb2-null mice having abnormal development of the cerebral cortex and cerebellum [27,28].…”

Section: Hj Wormanmentioning

confidence: 99%

Nuclear lamins and laminopathies

Worman¹

2011

The Journal of Pathology

357

322

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Nuclear lamins are intermediate filament proteins that polymerize to form the nuclear lamina on the inner aspect of the inner nuclear membrane. Long known to be essential for maintaining nuclear structure and disassembling/reassembling during mitosis in metazoans, research over the past dozen years has shown that mutations in genes encoding nuclear lamins, particularly LMNA encoding the A-type lamins, cause a broad range of diverse diseases, often referred to as laminopathies. Lamins are expressed in all mammalian somatic cells but mutations in their genes lead to relatively tissue-selective disease phenotypes in most cases. While mutations causing laminopathies have been shown to produce abnormalities in nuclear morphology, how these disease-causing mutations or resultant alterations in nuclear structure lead to pathology is only starting to be understood. Despite the incomplete understanding of pathogenic mechanisms underlying the laminopathies, basic research in cellular and small animal models has produced promising leads for treatments of these rare diseases.

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Section: Hj Wormanmentioning

confidence: 99%

Nuclear lamins and laminopathies

Worman¹

2011

The Journal of Pathology

357

322

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“…This hypothesis is supported by the studies that link mutations in mammalian B-type lamins with developmental disorders such as autosomal dominant leukodystrophy, premature cell senescence, and lipodystrophy (27)(28)(29), and by observation of defects suggesting accelerated aging and neuromuscular degeneration in the Drosophila mutant for the B-type lamin LamDm 0 (30). Moreover, even a wider spectrum of similar degenerative tissue-specific diseases has been associated with mutations in the nuclear envelope components interacting with both the B-and the A/C-type lamins, and in the A/C-type lamins themselves (31-38).…”

mentioning

confidence: 90%

The B-type lamin is required for somatic repression of testis-specific gene clusters

Shevelyov

Lavrov

Mikhaylova

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

123

118

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Large clusters of coexpressed tissue-specific genes are abundant on chromosomes of diverse species. The genes coordinately misexpressed in diverse diseases are also found in similar clusters, suggesting that evolutionarily conserved mechanisms regulate expression of large multigenic regions both in normal development and in its pathological disruptions. Studies on individual loci suggest that silent clusters of coregulated genes are embedded in repressed chromatin domains, often localized to the nuclear periphery. To test this model at the genome-wide scale, we studied transcriptional regulation of large testis-specific gene clusters in somatic tissues of Drosophila. These gene clusters showed a drastic paucity of known expressed transgene insertions, indicating that they indeed are embedded in repressed chromatin. Bioinformatics analysis suggested the major role for the B-type lamin, LamDmo, in repression of large testis-specific gene clusters, showing that in somatic cells as many as three-quarters of these clusters interact with LamDmo. Ablation of LamDmo by using mutants and RNAi led to detachment of testis-specific clusters from nuclear envelope and to their selective transcriptional up-regulation in somatic cells, thus providing the first direct evidence for involvement of the B-type lamin in tissue-specific gene repression. Finally, we found that transcriptional activation of the lamina-bound testis-specific gene cluster in male germ line is coupled with its translocation away from the nuclear envelope. Our studies, which directly link nuclear architecture with coordinated regulation of tissue-specific genes, advance understanding of the mechanisms underlying both normal cell differentiation and developmental disorders caused by lesions in the B-type lamins and interacting proteins.coexpressed genes ͉ nuclear lamina P revious studies by others and us have shown that many coexpressed tissue-specific genes are organized in large continuous clusters on chromosomes of diverse species (1-3), and similar clustering has been observed for the genes deregulated in diverse diseases (4-8). These findings imply that higherorder chromatin structure may be involved in regulation of extensive multigenic regions in both normal development and its pathological disruptions. In support of this suggestion, alterations in chromatin structure across large multigenic domains have been correlated to changes in gene expression (9-13). Repressed multigenic regions are frequently localized to nuclear periphery (14), and a number of studies linked derepression/ activation of genetic loci with their translocation away from the nuclear envelope (15-21). These observations suggest that tethering of genetic loci to nuclear lamina causes their silencing. Recent reports of repression of integrated transgenes and adjacent endogenous genes upon their artificial recruitment to the nuclear envelope (21, 22) support this hypothesis; however, similar studies on different loci did not show repression (23,24) indicating that silencing at nuclear ...

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“…As other patients with APL has no detectable mutations in the LMNB2 gene the relationship of the mutations in the LMNB2 gene to the etiology of the disease has not been fully established [64].…”

Section: Laminopathies Associated With Mutations In the B-type Laminsmentioning

confidence: 99%

Mouse models of the laminopathies

Stewart

Kozlov

Fong

et al. 2007

Experimental Cell Research

107

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The A and B type lamins are nuclear intermediate filament proteins that comprise the bulk of the nuclear lamina, a thin proteinaceous structure underlying the inner nuclear membrane. The A-type lamins are encoded by the lamin A gene (LMNA). Mutations in this gene have been linked to at least nine diseases, including the progeroid diseases Hutchinson-Gilford progeria and atypical Werner's syndromes, striated muscle diseases including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting adipose tissue deposition, diseases affecting skeletal development, and a peripheral neuropathy. To understand how different diseases arise from different mutations in the same gene, mouse lines carrying some of the same mutations found in the human diseases have been established. We, and others have generated mice with different mutations that result in progeria, muscular dystrophy, and dilated cardiomyopathy. To further our understanding of the functions of the lamins, we also created mice lacking lamin B1, as well as mice expressing only one of the Atype lamins. These mouse lines are providing insights into the functions of the lamina and how changes to the lamina affect the mechanical integrity of the nucleus as well as signaling pathways that, when disrupted, may contribute to the disease.

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Sequencing of the Reannotated LMNB2 Gene Reveals Novel Mutations in Patients with Acquired Partial Lipodystrophy

Cited by 180 publications

References 26 publications

Nuclear lamins and laminopathies

Nuclear lamins and laminopathies

The B-type lamin is required for somatic repression of testis-specific gene clusters

Mouse models of the laminopathies

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