A- and B-type lamins are differentially expressed in normal human tissues

Broers, Jos L. V.; Machiels, Barbie M.; Kuijpers, Helma J.H.; Smedts, Frank; Kieboom, Ronald van den; Raymond, Yves; Ramaekers, Frans C. S.

doi:10.1007/s004180050138

Cited by 248 publications

(245 citation statements)

References 27 publications

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“…All mammalian cells express at least one form of the B-type lamins, and the expression is constitutive during development; expression is detectable in ES cells as well as stem cells for the immune, hematopoeitic, and neuroendocrine systems (10,11,37,38). In contrast, A-type lamins cannot be detected in any cell type before day 7 or 8 of embryonic development (10,11,37).…”

Section: Discussionmentioning

confidence: 99%

Lamin B1 is required for mouse development and nuclear integrity

Vergnes

Péterfy

Bergö

et al. 2004

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

354

355

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Lamins are key structural components of the nuclear lamina, an intermediate filament meshwork that lies beneath the inner nuclear membrane. Lamins play a role in nuclear architecture, DNA replication, and gene expression. Mutations affecting A-type lamins have been associated with a variety of human diseases, including muscular dystrophy, cardiomyopathy, lipodystrophy, and progeria, but mutations in B-type lamins have never been identified in humans or in experimental animals. To investigate the in vivo function of lamin B1, the major B-type lamin, we generated mice with an insertional mutation in Lmnb1. The mutation resulted in the synthesis of a mutant lamin B1 protein lacking several key functional domains, including a portion of the rod domain, the nuclear localization signal, and the CAAX motif (the carboxylterminal signal for farnesylation). Homozygous Lmnb1 mutant mice survived embryonic development but died at birth with defects in lung and bone. Fibroblasts from mutant embryos grew under standard cell-culture conditions but displayed grossly misshapen nuclei, impaired differentiation, increased polyploidy, and premature senescence. Thus, the lamin B1 mutant mice provide evidence for a broad and nonredundant function of lamin B1 in mammalian development. These mutant mice and cell lines derived from them will be useful models for studying the role of the nuclear lamina in various cellular processes.nuclear envelope ͉ lamins ͉ knockout mice ͉ gene trapping T he nuclear lamina, a protein meshwork that lines the inner nuclear membrane, is critical in fundamental cellular processes, including nuclear organization, chromatin segregation, DNA replication, and gene transcription (1-5). The principal protein components of the lamina are lamins, which are members of the intermediate filament protein family. Like other intermediate filament proteins, lamins possess an aminoterminal head domain and a highly conserved central ␣-rod domain for polymerization and oligomerization (6). Lamins are, however, distinguished from other intermediate filament proteins by a nuclear localization motif. In addition, prelamin A and lamins B1 and B2 contain a carboxyl-terminal CAAX motif that triggers a series of posttranslational modifications (farnesylation, endoproteolytic trimming of the last three amino acid residues, and methylation of the newly exposed farnesylcysteine) (6). Aside from their structural role in the formation of the nuclear lamina, lamins A and C are found in the nucleoplasm adjacent to sites of DNA synthesis and RNA processing, suggesting that these proteins could influence both DNA replication and gene expression (2,7,8).In vertebrates, lamins are classified as A or B type, based on sequence homology, expression pattern, biochemical properties, and localization during mitosis. The A-type lamins, lamins A and C, are synthesized from alternatively spliced transcripts of LMNA and are expressed in most differentiated cells (9). Somatic cells also express two B-type lamins, lamin B1 and lamin B2, which are encode...

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Section: Discussionmentioning

confidence: 99%

Lamin B1 is required for mouse development and nuclear integrity

Vergnes

Péterfy

Bergö

et al. 2004

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

354

355

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“…Lamins A and C, which are splice variants differing in their C-termini, usually appear at the time of, or following differentiation (reviewed in [1]) whereas lamins B1 and B2 are expressed throughout development, albeit at varying levels [64]. This developmental regulation is likely to be important as it is observed in all vertebrates tested (frogs, birds, mammals) as well as in Drosophila (reviewed in [1]).…”

Section: A Different Ne Proteome For Different Tissues?mentioning

confidence: 99%

“…These observations support the hypothesis that each cell type has a small set of unique or preferentially expressed NE proteins. Thus, analysis of NEs from other tissues is predicted to identify some additional NE transmembrane proteins that are absent from liver.The first indication that NE composition might be dynamic came from observations that lamin subtypes change in their expression during development.Lamins A and C, which are splice variants differing in their C-termini, usually appear at the time of, or following differentiation (reviewed in [1]) whereas lamins B1 and B2 are expressed throughout development, albeit at varying levels [64]. This developmental regulation is likely to be important as it is observed in all vertebrates tested (frogs, birds, mammals) as well as in Drosophila (reviewed in [1]).…”

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confidence: 99%

The nuclear membrane proteome: extending the envelope

Schirmer

Gerace

2005

Trends in Biochemical Sciences

128

109

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The marriage of proteomics with cell biology has produced extensive inventories of the proteins that inhabit several subcellular organelles. Recent proteomic analysis has identified a large number of new putative transmembrane proteins in the nuclear envelope, and transcriptome profiling suggests that the nuclear membrane proteome exhibits some significant variations among different tissues. Cell type-specific differences in the composition of protein subcomplexes of the nuclear envelope, particularly those containing the disease-associated protein lamin A, could yield distinctive functions and so explain the tissue-specificity of a diverse group of nuclear envelope-linked disorders in humans. Considered together, these recent results suggest an unexpected functional complexity at the nuclear envelope.3 An introduction to the nuclear envelopeThe past few years have seen an explosion in the number of identified nuclear envelope (NE) proteins as well as in the number of their associated diseases. The NE (Figure 1), which is continuous with the more peripheral ER, contains an outer (ONM) and inner nuclear membrane (INM) that are joined at the nuclear pore membrane, giving rise to three different subdomains within nuclear membranes. The ONM is functionally similar to the more peripheral ER, but also is thought to contain some distinct resident proteins. The INM contains a large group of distinctive transmembrane proteins and is lined by a polymer of intermediate filament proteins called lamins. As many as four major lamin subtypes (lamin A, C, B1, and B2) are expressed in mammalian cells in a developmentally-regulated manner. Most lamin subtypes can be modified with lipid moieties that facilitate their targeting to the NE, and a fraction of some lamins occurs in the nucleoplasm as well as at the INM (reviewed in [1]). The lamin polymer and interacting proteins at the INM collectively comprise the nuclear lamina. The nuclear pore membrane is closely associated with nuclear pore complexes (NPCs), the main macromolecular transport channels across the NE. The transport functions and proteome of the NPC have been extensively characterized [2,3], and will not be further considered here. It is generally agreed that the lamina has a role in nuclear morphology and stability [4][5][6], and support for a wide and ever-increasing array of additional functions has emerged from recent studies. Lamins and lamina-associated membrane proteins have been linked to activities as diverse as transcription [7][8][9][10], DNA replication [11,12], nuclear anchoring/ migration within the cell [13], and signaling cascades [14]. To what extent these are direct or indirect effects of lamina proteins remains to be elucidated. 4Consistent with the notion that the nuclear lamina is involved in a diverse range of basic cellular functions, at least fifteen inherited diseases and syndromes have been linked to lamins A/C and certain associated NE transmembrane proteins.These include muscular dystrophies, lipodystrophies, neuropathy, cardiomyo...

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“…LMNA, located on chromosome 1q21.2, encodes a nuclear envelope protein that exists as a heterodimer of lamin A and lamin C and is expressed in several cell types including liver, fat, muscle, and pancreas. 27 35 Huchinson-Gilford progeria (OMIM 176670), 36 -38 and autosomal dominant and recessive forms of Charcot Marie tooth disease (OMIM 605588). [39][40] The mechanism whereby mutations in LMNA lead to these diverse phenotypes is presently unknown.…”

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confidence: 99%

Variation in the Lamin A/C Gene

Steinle

Kazlauskaite

Imumorin

et al. 2004

ATVB

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Objective— Metabolic syndrome is associated with increased risk for cardiovascular disease and type 2 diabetes mellitus (T2DM). The lamin A/C ( LMNA ) gene, mutations of which cause rare syndromes of severe insulin resistance and dyslipidemia, is located on chromosome 1q21-q24, a region linked to T2DM in several genome wide scans, including in the Old Order Amish. To determine whether polymorphisms in LMNA influence susceptibility to metabolic syndrome and its constituent components. Methods and Results— We performed DNA sequence analysis of LMNA . Six single-nucleotide polymorphisms (SNPs) were identified: c.141889C>T (intron 3), c.141906G>T (intron 3), A287A (c.141253T>C; exon 5), c.140353G>A (intron 6), c.139418C>T (intron 8), and H566H (c. 138747C>T; exon 10). In 971 participants from the Amish Family Diabetes Study, the H566H polymorphism of LMNA was associated with metabolic syndrome diagnosed according to National Cholesterol Education Program ATP III criteria and also higher mean fasting triglyceride and lower mean high-density lipoprotein-cholesterol concentrations. However, no differences in allele frequencies were observed for any SNP among participants with T2DM or impaired glucose homeostasis (IGH) and normoglycemic controls. Haplotype analysis showed that >87% of individuals carried 1 of 2 common LMNA haplotypes. There were no significant differences in haplotype frequencies among subjects with metabolic syndrome T2DM, IGH, and controls. Conclusion— Sequence variation in LMNA may confer modest susceptibility for development of metabolic syndrome and dyslipidemia in the Amish.

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A- and B-type lamins are differentially expressed in normal human tissues

Cited by 248 publications

References 27 publications

Lamin B1 is required for mouse development and nuclear integrity

Lamin B1 is required for mouse development and nuclear integrity

The nuclear membrane proteome: extending the envelope

Variation in the Lamin A/C Gene

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