Abstract
Hutchinson-Gilford progeria syndrome and Werner syndrome are two of the best characterized human progeroid diseases with clinical features mimicking physiological aging at an early age. Both disorders have been the focus of intense research in recent years since they might provide insights into the pathology of normal human aging. The chapter contains a detailed description of the clinical features of both disorders and then it focuses on the genetics, the resulting biochemical alterations at the protein level and the most recent findings and hypotheses concerning the molecular basis of the premature aging phenotypes. A description of available diagnostic and therapeutic approaches is included.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Navarro CL, Cau P, Lévy N. Molecular bases of progeroid syndromes. Hum Mol Genet 2006; 15:R151–161.
Kudlow BA, Kennedy BK, Monnat RJ Jr. Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat Rev Mol Cell Biol 2007; 8:394–404.
Ding SL, Shen CY. Model of human aging: recent findings on Werner’s and Hutchinson-Gilford progeria syndromes. Clin Interv Aging 2008; 3:431–444.
Pollex RL, Hegele RA. Hutchinson-Gilford progeria syndrome. Clin Genet 2004; 66:375–381.
Satoh M, Imai M, Sugimoto M et al. Prevalence of Werner’s syndrome heterozygotes in Japan. Lancet 1999; 353:1766.
Goto M. Clinical aspects of Werner’s syndrome: Its natural history and the genetics of the disease. In: Lebel M, ed. Molecular Mechanisms of Werner’s Syndrome. New York: Kluver Academic Plenum Publishers, 2004:1–11.
Masala MV, Scapaticci S, Olivieri C et al. Epidemiology and clinical aspects of Werner’s syndrome in North Sardinia: description of a cluster. Eur J Dermatol 2007; 17:213–216.
Hutchinson J. Congenital absence of hair and mammary glands with atrophic condition of the skin and its appendages. Trans Med Chir Soc Edinburgh 1886; 69:473–477.
Gilford H. On a condition of mixed premature and immature development. Med Chirurg Trans 1987; 80:17–45.
Gilford H. Progeria: A form of senilism. Practitioner 1904; 73:188–217.
Gordon LB, McCarten KM, Giobbie-Hurder A et al. Disease progression in Hutchinson-Gilford progeria syndrome: impact on growth and development. Pediatrics 2007; 120:824–833.
Brown WT, Gordon LB, Collins FS. Hutchinson-Gilford Progeria syndrome. In: Pagon RA, Bird TC, Dolan CR et al, eds. GeneReviews [Internet]. Seattle: University of Washington, Seattle; 1993–2003 [updated 2006].
Hennekam RC. Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A 2006; 140:2603–2624.
Pereira S, Bourgeois P, Navarro C et al. HGPS and related premature aging disorders: from genomic identification to the first therapeutic approaches. Mech Ageing Dev 2008; 129:449–459.
Muftuoglu M, Oshima J, von Kobbe C et al. The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis. Hum Genet 2008; 124:369–377.
Goto M. Hierarchical deterioration of body systems in Werner’s syndrome: implications for normal ageing. Mech Ageing Dev 1997; 98:239–254.
Epstein CJ, Martin GM, Schultz AL et al. Werner’s syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine (Baltimore) 1966; 45:177–221.
Huang S, Lee L, Hanson NB et al. The spectrum of WRN mutations in Werner syndrome patients. Hum Mutat 2006; 27:558–567.
Ishikawa Y, Sugano H, Matsumoto T et al. Unusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race. Cancer 1999; 85:1345–1352.
Leistritz DF, Hanson N, Martin GM et al. Werner Syndrome. In: Pagon RA, Bird TC, Dolan CR et al, eds. GeneReviews [Internet]. Seattle: University of Washington, 1993–2002 [updated 2007].
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.
De Sandre-Giovannoli A, Bernard R, Cau P et al. Lamin a truncation in Hutchinson-Gilford progeria. Science 2003; 300:2055.
Machiels BM, Zorenc AH, Endert JM et al. An alternative splicing product of the lamin A/C gene lacks exon 10. J Biol Chem 1996; 271:9249–9253.
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 2009; 17:928–937.
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.
Wuyts W, Biervliet M, Reyniers E et al. Somatic and gonadal mosaicism in Hutchinson-Gilford progeria. Am J Med Genet A 2005; 135:66–68.
Jacob KN, Garg A. Laminopathies: multisystem dystrophy syndromes. Mol Genet Metab 2006; 87:289-302. 30._Fukuchi K, Katsuya T, Sugimoto K et al. LMNA mutation in a 45 year old Japanese subject with Hutchinson-Gilford progeria syndrome. J Med Genet 2004; 41:e67.
Shalev SA, De Sandre-Giovannoli A, Shani AA et al. An association of Hutchinson-Gilford progeria and malignancy. Am J Med Genet A 2007; 143A:1821–1826.
Navarro CL, De Sandre-Giovannoli A, Bernard R et al. Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Hum Mol Genet 2004; 13:2493–503.
Navarro CL, Cadiñanos J, De Sandre-Giovannoli A et al. Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors. Hum Mol Genet 2005; 14:1503–1513.
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.
Denecke J, Brune T, Feldhaus T et al. A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson-Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS. Hum Mutat 2006; 27:524–531.
Plasilova M, Chattopadhyay C, Pal P et al. Homozygous missense mutation in the lamin A/C gene causes autosomal recessive Hutchinson-Gilford progeria syndrome. J Med Genet 2004; 41:609–614.
Liang L, Zhang H, Gu X. Homozygous LMNA mutation R527C in atypical Hutchinson-Gilford progeria syndrome: evidence for autosomal recessive inheritance. Acta Paediatr 2009; 98:1365–1368.
Verstraeten VL, Broers JL, van Steensel MA et al. Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation. Hum Mol Genet 2006; 15:2509–2522.
Garg A, Subramanyam L, Agarwal AK et al. Atypical progeroid syndrome due to heterozygous missense LMNA mutations. J Clin Endocrinol Metab 2009; 94:4971–4983.
Huang S, Lee L, Hanson NB et al. The spectrum of WRN mutations in Werner syndrome patients. Hum Mutat 2006; 27:558–567.
Chen L, Lee L, Kudlow BA et al. LMNA mutations in atypical Werner’s syndrome. Lancet 2003; 362:440–445.
Dechat T, Pfleghaar K, Sengupta K et al. Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. Genes Dev 2008; 22:832–853.
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.
Young SG, Meta M, Yang SH et al. Prelamin A farnesylation and progeroid syndromes. J Biol Chem 2006; 281:39741–39745.
Scaffidi P, Misteli T. Lamin A-dependent nuclear defects in human aging. Science 2006; 312:1059–1063.
Cao K, Capell BC, Erdos MR et al. 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.
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.
Liu B, Wang J, Chan KM et al. Genomic instability in laminopathy-based premature aging. Nat Med 2005; 11:780–785.
Liu Y, Rusinol A, Sinensky M et al. DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A. J Cell Sci 2006; 119:4644–4649.
Liu Y, Wang Y, Rusinol AE et al. Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A. FASEB J 2008; 22:603–611.
Musich PR, Zou Y. Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A. Aging 2009; 1:28–37.
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.
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.
Decker ML, Chavez E, Vulto I et al. Telomere length in Hutchinson-Gilford progeria syndrome. Mech Ageing Dev 2009; 130:377–383.
Bruston F, Delbarre E, Ostlund C et al. Loss of a DNA binding site within the tail of prelamin A contributes to altered heterochromatin anchorage by progerin. FEBS Lett 2010; 584:2999–3004.
Benson EK, Lee SW, Aaronson SA. Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence. J Cell Sci 2010; [Epub ahead of print].
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 2007; 104:4955–4960.
Scaffidi P, Misteli T. Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing. Nat Cell Biol 2008; 10:452–459.
Halaschek-Wiener J, Brooks-Wilson A. Progeria of stem cells: stem cell exhaustion in Hutchinson-Gilford progeria syndrome. J Gerontol A Biol Sci Med Sci 2007; 62:3–8.
Dahl KN, Scaffidi P, Islam MF et al. Distinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci USA 2006; 103:10271–10276.
Verstraeten VL, Ji JY, Cummings KS et al. Increased mechanosensitivity and nuclear stiffness in Hutchinson-Gilford progeria cells: effects of farnesyltransferase inhibitors. Aging Cell 2008; 7:383–393.
Melcher R, von Golitschek R, Steinlein C et al. Spectral karyotyping of Werner syndrome fibroblast cultures. Cytogenet. Cell Genet 2000; 91:180–185.
Yu CE, Oshima J, Wijsman EM et al. Mutations in the consensus helicase domains of the Werner syndrome gene. Werner’s Syndrome Collaborative Group. Am J Hum Genet 1997; 60:330–341.
Rossi ML, Ghosh AK, Bohr VA. Roles of Werner syndrome protein in protection of genome integrity. DNA Repair 2010; 9:331–344.
Coppedè F, Migliore L. DNA repair in premature aging disorders and neurodegeneration. Curr Aging Sci 2010; 3:3–19.
Haustein J, Pawlas U, Cervos-Navarro J. The Werner syndrome: a case study. Clin Neuropathol 1989; 8:147–151.
Leverenz JB, Yu CE, Schellenberg GD. Aging-associated neuropathology in Werner syndrome. Acta Neuropathol 1998; 96:421–424.
Mori H, Tomiyama T, Maeda N et al. Lack of amyloid plaque formation in the central nervous system of a patient with Werner syndrome. Neuropathology 2003; 23:51–56.
Payão SL, de Labio RW, Gatti LL et al. Werner helicase polymorphism is not associated with Alzheimer’s disease. J Alzheimers Dis 2004; 6(6):591–4; discussion 673–681.
Anderson NE, Haas LF. Neurological complications of Werner’s syndrome. J Neurol 2003; 250: 1174–1178.
Malandrini A, Dotti MT, Villanova M. Neurological involvement in Werner’s syndrome: clinical and biopsy study of a familial case. Eur Neurol 2000; 44:187–189.
Umehara F, Abe M, Nakagawa M et al. Werner’s syndrome associated with spastic paraparesis and peripheral neuropathy. Neurology 1993; 43:1252–1254.
Just A, Canaple S, Joly H et al. Neurologic complications in a case of Werner syndrome. Rev Neurol (Paris) 1996; 152:634–636.
Kawamura H, Mori S, Murano S et al. Werner’s syndrome associated with progressive subcortical vascular encephalopathy of the Binswanger type. Nippon Ronen Igakkai Zasshi 1999; 36:648–651.
Varela I, Pereira S, Ugalde AP et al. Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat Med 2008; 14:767–772.
Osorio FG, Obaya AJ, López-Otín C et al. Accelerated ageing: from mechanism to therapy through animal models. Transgenic Res 2009; 18:17–15.
Worman HJ, Fong LG, Muchir A et al. Laminopathies and the long strange trip from basic cell biology to therapy. J Clin Invest 2009; 119:1825–1836.
Massip L, Garand C, Paquet ER et al. Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB J 2010; 24:158–217.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Landes Bioscience and Springer Science+Business Media
About this chapter
Cite this chapter
Coppedè, F. (2012). Premature Aging Syndrome. In: Ahmad, S.I. (eds) Neurodegenerative Diseases. Advances in Experimental Medicine and Biology, vol 724. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0653-2_24
Download citation
DOI: https://doi.org/10.1007/978-1-4614-0653-2_24
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-0652-5
Online ISBN: 978-1-4614-0653-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)