Abstract
Most cases of the segmental progeroid syndrome, Hutchinson–Gilford progeria syndrome (HGPS), are caused by a de novo dominant mutation within a single codon of the LMNA gene. This mutation leads to the increased usage of an internal splice site that generates an alternative lamin A transcript with an internal deletion of 150 nucleotides, called lamin AΔ150. The LMNA gene encodes two major proteins of the inner nuclear lamina, lamins A and C, but not much is known about their expression levels. Determination of the overall expression levels of the LMNA gene transcripts is an important step to further the understanding of the HGPS. In this study, we have performed absolute quantification of the lamins A, C and AΔ150 transcripts in primary dermal fibroblasts from HGPS patients and unaffected age-matched and parent controls. We show that the lamin AΔ150 transcript is present in unaffected controls but its expression is >160-fold lower than that in samples from HGPS patients. Analysis of transcript expression during in vitro aging shows that although the levels of lamin A and lamin C transcripts remain unchanged, the lamin AΔ150 transcript increases in late passage cells from HGPS patients and parental controls. This study provides a new method for LMNA transcript analysis and insights into the expression of the LMNA gene in HGPS and normal cells.
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References
Martin GM : Genetic modulation of senescent phenotypes in Homo sapiens. Cell 2005; 120: 523–532.
Pollex RL, Hegele RA : Hutchinson–Gilford progeria syndrome. Clin Genet 2004; 66: 375–381.
De Sandre-Giovannoli A, Bernard R, Cau P et al: Lamin a truncation in Hutchinson–Gilford progeria. Science 2003; 300: 2055.
Eriksson M, Brown WT, Gordon LB et al: Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 2003; 423: 293–298.
Goldman RD, Gruenbaum Y, Moir RD, Shumaker DK, Spann TP : Nuclear lamins: building blocks of nuclear architecture. Genes Dev 2002; 16: 533–547.
Fisher DZ, Chaudhary N, Blobel G : cDNA sequencing of nuclear lamins A and C reveals primary and secondary structural homology to intermediate filament proteins. Proc Natl Acad Sci USA 1986; 83: 6450–6454.
Rober RA, Weber K, Osborn M : Differential timing of nuclear lamin A/C expression in the various organs of the mouse embryo and the young animal: a developmental study. Development 1989; 105: 365–378.
Machiels BM, Zorenc AH, Endert JM : An alternative splicing product of the lamin A/C gene lacks exon 10. J Biol Chem 1996; 271: 9249–9253.
Furukawa K, Inagaki H, Hotta Y : Identification and cloning of an mRNA coding for a germ cell-specific A-type lamin in mice. Exp Cell Res 1994; 212: 426–430.
Beck LA, Hosick TJ, Sinensky M : Isoprenylation is required for the processing of the lamin A precursor. J Cell Biol 1990; 110: 1489–1499.
Capell BC, Collins FS : Human laminopathies: nuclei gone genetically awry. Nat Rev Genet 2006; 7: 940–952.
Sinensky M, Fantle K, Trujillo M, McLain T, Kupfer A, Dalton M : The processing pathway of prelamin A. J Cell Sci 1994; 107: 61–67.
Dechat T, Shimi T, Adam SA et al: Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging. Proc Natl Acad Sci USA 2006; 104: 4955–4960.
Goldman RD, Shumaker DK, Erdos MR et al: Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome. Proc Natl Acad Sci USA 2004; 101: 8963–8968.
Shumaker DK, Dechat T, Kohlmaier A et al: Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci USA 2006; 103: 8703–8708.
Ly DH, Lockhart DJ, Lerner RA, Schultz PG : Mitotic misregulation and human aging. Science 2000; 287: 2486–2492.
Csoka AB, English SB, Simkevich CP et al: Genome-scale expression profiling of Hutchinson–Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis. Aging Cell 2004; 3: 235–243.
Cao K, Capell BC, Erdos MR, Djabali K, Collins FS : A lamin A protein isoform overexpressed in Hutchinson–Gilford progeria syndrome interferes with mitosis in progeria and normal cells. Proc Natl Acad Sci USA 2007; 104: 4949–4954.
Haithcock E, Dayani Y, Neufeld E et al: Age-related changes of nuclear architecture in Caenorhabditis elegans. Proc Natl Acad Sci USA 2005; 102: 16690–16695.
Scaffidi P, Misteli T : Lamin A-dependent nuclear defects in human aging. Science 2006; 312: 1059–1063.
McClintock D, Ratner D, Lokuge M et al: The mutant form of lamin A that causes Hutchinson–Gilford progeria is a biomarker of cellular aging in human skin. PLoS ONE 2007; 2: e1269.
Hayflick L : The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 1965; 37: 614–636.
Brown WT : Genetic diseases of premature aging as models of senescence. Annu Rev Gerontol Geriatr 1990; 10: 23–42.
Rozen S, Skaletsky H : Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 2000; 132: 365–386.
Eriksson M : Real-time RT-PCR for CTG repeat-containing genes. Methods Mol Biol 2004; 277: 77–84.
Sagelius H, Rosengardten Y, Hanif M et al: Targeted transgenic expression of the mutation causing Hutchinson–Gilford progeria syndrome leads to proliferative and degenerative epidermal disease. J Cell Sci 2008; 121: 969–978.
Nagasaka Y, Dillner K, Ebise H et al: A unique gene expression signature discriminates familial Alzheimer's disease mutation carriers from their wild-type siblings. Proc Natl Acad Sci USA 2005; 102: 14854–14859.
Moulson CL, Fong LG, Gardner JM et al: Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes. Hum Mutat 2007; 28: 882–889.
Reddel CJ, Weiss AS : Lamin A expression levels are unperturbed at the normal and mutant alleles but display partial splice site selection in Hutchinson-Gilford progeria syndrome. J Med Genet 2004; 41: 715–717.
Reff M, Schneider EL : Cell culture aging. Mol Cell Biochem 1981; 36: 169–176.
McClintock D, Gordon LB, Djabali K : Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-lamin A G608G antibody. Proc Natl Acad Sci USA 2006; 103: 2154–2159.
Verstraeten VL, Ji JY, Cummings KS, Lee RT, Lammerding J : Increased mechanosensitivity and nuclear stiffness in Hutchinson–Gilford progeria cells: effects of farnesyltransferase inhibitors. Aging Cell 2008; 7: 383–393.
Acknowledgements
We thank Mubashir Hanif for his expert technical assistance, and Karin Dillner and Caroline Graff for their helpful discussions on assay design. This study was supported by grants from the Gun and Bertil Stohne Foundation, the Åke Wiberg Foundation, the Magnus Bergvall Foundation, the Tore Nilsson Foundation, the Loo and Hans Osterman Foundation, the Torsten and Ragnar Söderberg Foundations, the Jeansson Foundations, the Swedish Medical Research Council and the Swedish Foundation for Strategic Research.
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Rodriguez, S., Coppedè, F., Sagelius, H. et al. Increased expression of the Hutchinson–Gilford progeria syndrome truncated lamin A transcript during cell aging. Eur J Hum Genet 17, 928–937 (2009). https://doi.org/10.1038/ejhg.2008.270
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DOI: https://doi.org/10.1038/ejhg.2008.270
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