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MEDICINE REVIEW ARTICLE Progeroid Syndromes Clinical Symptoms and Molecular Causes of Premature Aging Gregor Hirschfeld, Mark Berneburg, Christine von Arnim, Sebastian Iben, Albert C. Ludolph, Karin Scharffetter-Kochanek SUMMARY Introduction: Progeroid syndromes are caused by single gene mutations and comprise a group of diseases characterized by signs of premature aging. Clinical symptoms of premature aging are skin atrophy with loss of cutaneous elasticity, mottled pigmentation, dysfunction of cutaneous appendices and of the central nervous system, degeneration, and an increased susceptibility for malignant tumors. Methods: Selective literature review. Results: At a molecular level, there are clear correlations between premature aging and impaired function of proteins involved in DNA repair, cell cycle control, apoptosis, and gene expression. The numerous premature aging syndromes include Xeroderma pigmentosum, Werner syndrome, ataxia telangiectasia, Cockayne syndrome, Hutchinson Gilford syndrome, Fanconi syndrome and Bloom and Rothmund Thomson syndrome. The understanding of these syndromes has improved significantly. They are characterized by genomic instabilities of varying aetiologies in various different genes, and result in accelerated aging, tumors of the skin and other organs, severe neurodegenerative symptoms, arteriosclerosis, cachexia and impaired tumor defense by the immune system. Research on progeroid syndromes supports the importance of the maintenance of genomic stability as an important antidote to aging and tumor formation. Dtsch Arztebl 2007; 104(6): A 346–53. Key words: progeria, molecular medicine, gene mutation, aging process, Hutchinson Gilford syndrome I t was in 1886 that a clinical aging syndrome was first described, which began in early childhood and ended in death at age 13–17. This illness was called progeria or Hutchinson Gilford Syndrome. More than 75 syndromes involving symptoms of premature aging are now recognized, known as progeroid syndromes, by analogy with progeria. Unimodal progeroid syndromes affect a single organ, and segmental progeroid syndromes affect several organs. The segmental progeroid syndromes have in common the simultaneous onset of premature aging in several organs, such as skin, the skeletal system with osteoporosis and degenerative joint disease, of the vascular system, of the metabolic system with diabetes mellitus, noticeable atrophy of subcutaneous fat, neurodegenerative diseases, increased incidence of various tumors, immunological senescence, increased incidence of autoimmune diseases, and increased susceptibility to infection (1, 2). Progeroid syndromes are characterized by mutations in the germ cell line, which affect all organs. A given mutation has a different effect in a postmitotic organ such as the nervous system than in mitotic tissue such as connective tissue, epithelially based organs, or the blood. The effect depends on which DNA repair mechanism is predominant in the affected organ. The clinical criteria for premature aging in progeroid syndromes are summarized generally in box 1. Most recent data are available on internet databases (3–6). In recent years, the molecular and genetic understanding of aging syndromes has improved markedly. Cells from progeroid patients react to the slightest of DNA damaging stimuli such as ultraviolet or ionizing radiation or high concentrations of reactive oxygen species with cell cycle arrest, apoptosis or genomic instability. Underlying this pattern of reactions are among other things qualitative and quantitative defects in DNA repair and genomic stability. Research into progeroid syndromes aids the understanding of the close interplay between DNA repair, transcription and translation processes, cell cycle control, apoptosis and key factors in physiological aging and tumorigenesis (7–9). Universitätsklinik für Dermatologie und Allergologie, Universitätsklinikum Ulm (Dr. med. Hirschfeld, Dr. med. Iben, Prof. Dr. med. ScharffetterKochanek); Universitäts-Hautklinik der Eberhard-Karls-Universität Tübingen (PD Dr. med. Berneburg); Universitätsklinik für Neurologie, Rehabilitationskrankenhaus Ulm (PD Dr. med. von Armin, Prof. Dr. med. Ludolph) Dtsch Arztebl 2007; 104(6): A 346–53 ⏐ www.aerzteblatt.de 1 MEDICINE Although progeroid syndromes depart from physiological aging processes in their detail, these disease models nevertheless provide usefully generalizable insight into aging processes. This article offers an overview of differing aging phenotypes in progeroid syndromes. Xeroderma pigmentosum Xeroderma pigmentosum patients show premature aging of the skin with fibrosis, atrophy, inhomogeneous pigmentation and increased numbers of solar lentigines (figure 1). Patients develop spinocellular carcinomas, basal cell carcinomas, Merkel cell carcinomas, and melanomas, in response to sun exposure, during childhood. The disease has a prevalence of 1 : 40 000 to 1 : 100 000 and is inherited in an autosomal recessive pattern. The gene loci of the complementation groups XPA–XPG are located on chromosomes 3, 9, 11, 16, and 19. The defects affect genes which code for nucleotide excision repair (NER) proteins (10). Because of their UV sensitivity, these patients require thoroughgoing sun protection with the highest protection factor. Smoking leads to bronchial carcinoma at a young age. This disease serves as a model for disordered DNA repair, which leads both to skin aging and mutation in genes controlling the cell cycle, and in tumor suppressor genes, and in turn to skin cancers. This disease entity has already contributed to the better understanding of the role of senescent or prematurely aged connective tissue in tumor progression and metastasis. The principles of damaged nucleotide excision repair in xeroderma pigmentosum (XP) are shown in diagram 1 (11). The complementation groups in xeroderma pigmentosum are marked XPA to XPG, and represent mutated nucleotide excision repair proteins. In defects of XPC, XPA or XPE, the recognition of UV damaged DNA is disrupted (diagram 1). In defects of the helicases XPB and XPD, the DNA can no longer be separated, and the access of endonucleases is disrupted. The smallest UV radiation doses can trigger programmed cell death of keratinocytes and other skin cells, in xeroderma pigmentosum. This correlates with the clinical finding of marked photosensitivity. The increase in apoptosis induction is protective against tumors, albeit without eliminating every single malignant transformed BOX 1 Criteria of premature aging in progeroid syndromes > Clinical criteria – One or more tumors which are typical in an older agegroup – Premature greying of the hair and/or hair loss – Dementia and/or marked neurodegenerative symptoms – Increased susceptibility to slow virus diseases – Pigment disorders in the skin – Regional fibrosis in the skin – Diabetes mellitus – Disorders of lipid metabolism – Changes in the volume and distribution of adipose tissue – Hypogonadism – Autoimmune phenomena – Degenerative vascular disease and arterial hypertension – Osteoporosis – Degenerative joint changes – Cataracts > Genetic Criteria – Genomic instability with increased intrinsic mutagenesis and clustering of non-constitutional chromosomal aberrations – The demonstration of a defect in a stem cell population or in the proliferation of stem cells – Mitochondrial changes in one or more tissues Dtsch Arztebl 2007; 104(6): A 346–53 ⏐ www.aerzteblatt.de 2 MEDICINE Figure 1: Clinial picture in xeroderma pigmentosum. Solar lentigines appear in sun-exposed areas from early childhood. Later hypo and hyperpigmentation and the development of skin neoplasia. cell. DNA repair defects and immunosuppression are responsible for the 1 000 fold mortality due to UV B dependent skin carcinomas seen in xeroderma pigmentosum, such as spinocellular carcinoma, melanoma and basal cell carcinoma, before the end of the third decade of life. Cockayne syndrome Cockayne syndrome patients show progressive neurodegeneration, psychomotoric developmental delay, failure to thrive, and increasing cachexia with dry, wrinkled and photosensitive skin. Patients die of the sequelae of neurodegeneration with widespread demyelinization and calcification in the cerebrum, brain stem and cerebellum during the first two decades of life. The disease has an incidence of 1 : 250 000 and is inherited in an autosomal recessive pattern. The disease may be based on mutations in one of two genes, which lie on chromosomes 5 and 10 respectively. The underlying cause are mutations in the multifunctional proteins CSA and CSB, which are key components of the RNA polymerase complexes I to II. Defects in CSA and CSB inhibit transcription-coupled repair and transcription (12). The presence of neurodegenerative changes supports the hypothesis that metabolically active cerebral cells accumulate DNA damage through reactive oxygen species of mitochondrial origin, because they are inadequately repaired. DNA lesions block transcription and reduced transcription-coupled DNA repair leads to disordered neuronal differentiation. A further cause of neurodegeneration is the increased apoptosis of neurons through irreparable DNA damage. The removal of genetically unstable cells prevents the development of malignant tumors, but leads to neurodegeneration, because the level of cellular regeneration in an actively dividing pool of cells is inadequate in the largely postmitotic neural tissue. Around 20% of all XP patients suffer neurodegenerative change. XP patients have a ten fold risk of neural tumors, predominantly astrocytomas, medulloblastomas and schwannomas. Trichothiodystrophy The clinical phenotype of this disease is variable, and the full syndrome is described with the acronym (P)IBIDS: photosensitivity (in 50% of cases), intellectual impairment, brittle hair (cysteine deficient, brittle, hair with longitudinal splits), decreased fertility, and short stature. The disease is autosomal recessively inherited. The mutations, as in xeroderma Dtsch Arztebl 2007; 104(6): A 346–53 ⏐ www.aerzteblatt.de 3 MEDICINE DIAGRAM 1 Mechanism of nucleotide excision repair (NER). The first step is damage recognition, which occurs as part of transcription coupled repair (TCR). The transcribing polymerase (RNA Pol.) stops at the site of damage and activates further repair proteins. This process takes place very quickly, because it only takes in actively transcribing genes. The recognition of damage in the remainder of the genome (GGR, "global genome repair") is a slower process. Here, the damage is picked up by a protein complex with the XPC protein. Both recognition mechanisms recruit the xeroderma pigmentosum complementation group A (XPA) protein in order to verify the damage and the replication protein A (RPA) which marks the undamaged DNA strand. It is well known that Cockayne syndrome A and B proteins are involved in TCR. The precise interaction with other proteins has not yet been fully elucidated. During strand separation, both helicases XPB and XPD open the DNA for binding with other proteins. XPB and XPD are components of the basal transcription factor TFIIH, which is involved in DNA repair and in basal transcription of genes. At the point of incision, two endonucleases bind to the damaged DNA strand. The protein complex made up of excision repair complement complex (ERCC) 1 and XPF attaches at the 5´ end and XPG at the 3´ end. This allows the damaged strand to be removed and broken down. During neosynthesis of the missing DNA segment, the DNA is copied by a protein complex consisting of replication factors C (RFC), proliferating cell nuclear antigen (PCNA) and polymerase delta (Pol d) by reading the complementary and non-damaged strand. pigmentosum, are in XPB und XPD. The helicases XPB and XPD are multifunctional proteins of nucleotide excision repair and transcription initiation: XPB und XPD are components of the basal transcription factor IIH, which interacts with RNA polymerase II (13). XPD mutations with disturbed and reduced transcription lead to trichothiodystrophy. An overview of the deficiency syndromes of nucleotide excision repair can be seen in the table. Werner syndrome Werner syndrome is characterized by partially fibrosed, partially atrophic skin with hyperkeratoses, changes of pigmentation, and atrophy of subcutaneous fat tissue with traceries of veins visible through the skin. Patients have short stature and a characteristic facial appearance with a prominent forehead (bird-like face), premature greying and hair loss. Atherosclerosis, diabetes mellitus and osteoporosis occur early. The disease manifests in adolescence. The diagnosis is made using primary and secondary criteria (box 2). Most patients die in their fifth decade of cardiovascular causes or malignant tumors. Of the malignancies, which occur in about 10% of patients, 50% are made up of bone and soft tissue sarcomas. Werner syndrome has a worldwide prevalence of 1 : 1 000 000. Its inheritance is autosomal recessive, and affects the Werner gene on chromosome 8. The underlying causes are defects in the gene of the helicase WRN, a DNA separation protein with exonuclease activity. Dtsch Arztebl 2007; 104(6): A 346–53 ⏐ www.aerzteblatt.de 4 MEDICINE TABLE Overview of deficiency syndromes of nucleotide excision repair Key clinical symptoms Xeroderma pigmentosum Cockayne Syndrome Trichothiodystrophy UV sensitivity ++ +/– +/– Irregular skin pigmentation and aged skin ++ – – Sulphur deficient, brittle hair and nails – – + Ichthyosis – – + Skin cancer ++ – – Neurodegeneration – ++ + Facial dysmorphia – + + Short stature +/– ++ + Hypogonadism – + + Gene defects XPA bis XPG*1 CSA, CSB*2 XPB, XPD*3 *1 Complementation groups in xeroderma pigmentosum which are responsible for repair proteins with DNA damage recognition function *2 Cockayne syndrome A and B proteins *3 Complementation groups in xeroderma pigmentosum which are responsible for repair proteins with DNA helicase function ++, marked; +, significant; +/–, moderate; –, not observed Around 90% of Werner syndrome patients have mutations in the Werner gene. The helicase WRN is involved in various DNA repair pathways and in the stabilization of telomeres (14). Werner syndrome has contributed importantly to the understanding of aging processes. In the first place, Werner syndrome points to the important role of genomic instability in many aging symptoms. Secondly, the inability of cells to replicate (replicative senescence) seems to have a role in observed wound healing disorders, atherosclerosis, and possibly other symptoms too. Thirdly, connective tissue seems to be particularly vulnerable, because it is particularly in organs rich in connective tissue that aging and the development of malignancy is most pronounced Bloom syndrome and Rothmund Thomson syndrome Bloom syndrome and Rothmund Thomson syndrome are characterized by diffuse skin atrophy with loss of elasticity and poikiloderma (mottling) with an increase in small vessels in sunexposed skin. Erythema arises from birth, at first on the face. By contrast with Werner's syndrome, marked UV sensitivity is characteristic. Spinocellular carcinomas and basal cell carcinomas can also occur. Some patients develop alopecia of the scalp, eyebrows and eyelids. In Bloom syndrome leukemias, lymphomas and common gastrointestinal tumors predominate. In Rothmund Thomson syndrome livedo reticularis-like erythematous lesions appear first on the face, then the extremities and buttocks, with sparing of the back. Patients are UV sensitive and develop poikiloderma, skeletal anomalies and bone tumors. The disease is rare, with only 300 cases described in the literature. Its inheritance pattern is autosomal recessive. The cause of Bloom syndrome lies in a defect of BLM helicase, and the cause of Rothmund Thomson syndrome (figure 2) lies in defects in RecQL4 helicase. These defects lead to chromosomal brittleness, the discovery of which was a breakthrough in the understanding of this disease. These diseases, too, are characterized by genomic instability and an increased tumor risk. The variable clinical course, of the helicase defects WRN, BLM and RTS is probably attributable to differences in tissue expression, substrate specificity, and interaction partners. Ataxia teleangiectasia This disease presents between the first and third year of life, and is characterized by cerebellar ataxia, oculocutaneous telangectasias, atrophic facial skin, sensitivity to ionizing Dtsch Arztebl 2007; 104(6): A 346–53 ⏐ www.aerzteblatt.de 5 MEDICINE BOX 2 Clinical characteristics of Werner syndrome > Primary criteria (onset from age 10) – Bilateral cataracts – Dermatological manifestations: partly fibrosed skin of skin atrophy, changes of pigmentation, ulceration, hyperkeratoses, subcutaneous atrophy of fat tissue and characteristic facies "bird-like face" – Short stature – Consanguinity with parents or relatives with similar symptoms – Premature greying and/or thinning of the hair > Secondary criteria – Diabetes mellitus – Hypogonadism (reduced fertility, testicular or ovarian atrophy) – Osteoporosis – Osteosclerosis of the distal phalanges of the fingers or toes on X-ray – Calcification of soft tissue – Indicators of premature atherosclerosis (e.g. history of myocardial infarction) – Mesenchymal, rare or multiple tumors – Unusual vocal range (shrill or sharp) – Pes planus > Reliable diagnosis – Requires one primary and two secondary criteria to be fulfilled > Probable diagnosis – The first three primary criteria and two other criteria are fulfilled > Possible diagnosis – Either cataracts or skin signs and four other criteria > Exclusion of diagnosis – Onset of symptoms before age 10 (with the exception of short stature) radiation, progressive humoral and cell-mediated immunodeficiency, hypogonadism and an 100 fold risk of lymphoma and leukemia. Patients die at the age of around 20. Ataxia teleangiectasia is an autosomal recessively inherited multi system disease with a prevalence of between 1 : 40 000 and 1 : 300 000. In this disease, there is a defect of the ATM gene (Ataxia teleangiectasia mutated) on chromosome 11. The protein kinase ATM acts as a signal transmitter, which activates repair proteins such as p53 following DNA double strand breaks. The molecular bases for this are summarized in an excellent review (15). Following ionizing radiation, cells arrest the cell cycle to repair DNA. Where ATM kinase is defective, the cell cycle continues despite the need for considerable repair. The missing activation of the DNA repair apparatus at least partially explains the genomic instability. Signalling by ATM kinase also appears to be important in the repair of telomeres. With the loss of ATM function, stem cells move into replicative senescence with shortened telomeres. This observation was important in explaining progressive neurodegenerative symptoms which characterize ataxia teleangiectasia, as part of a generalized stem cell proliferation defect. Hutchinson Gilford syndrome (progeria infantum) Affected children show signs of premature and accelerated aging from their first year of life in the form of failure to thrive with delayed dentition, diffuse alopecia, nail dystrophy, Dtsch Arztebl 2007; 104(6): A 346–53 ⏐ www.aerzteblatt.de 6 MEDICINE Figure 2: Clinical picture in Rothmund Thomson syndrome: the hand of a 19 year old patient is shown. Only the skin in light-esposed areas appear prematurely aged, with hyper and hypopigmentation and loss of elasticity. scleroderma-like skin changes, loss of subcutaneous fat tissue, atherosclerosis and an atrophic skin appearance consistent with old age. The life expectancy of progeria patients is around 13 years, with coronary and cerebral atherosclerosis the commonest cause of death. Hutchinson Gilford syndrome (HSG) is extremely rare, with an incidence of 1 : 4 to 1 : 8 Million. The disease arises for the most part in an autosomal dominant new mutation. Because the patients die before reaching reproductive age, the mutation disappears from the gene pool. The causes of HGS are mutations in the lamin gene on chromosome 1, which leads to wrong splicing of the RNA copy. The Lamin gene codes for four similar proteins, which arise via differential splicing of the RNA copy. Lamin proteins, as key components of the nuclear lamina, interact with the nuclear membrane and chromatin, and are responsible for the nuclear shape, the nuclear pore complex and organization of chromatin, regulation of DNA replication and Figure 3: Patient with the clinical phenotype of Werner syndrome, but without a demonstrable WRN helicase defect. This combination of findings is present in around 10% of these patients and suggests that gene products of other mutations can interact with the WRN protein or that other similar DNA repair pathways are involved. Dtsch Arztebl 2007; 104(6): A 346–53 ⏐ www.aerzteblatt.de 7 MEDICINE Figure 4: Young adult with Fanconi anemia and typical clinical symptoms such as short stature and microcephaly with normal intelligence and poikiloderma. The appearance of multiple invasive spinocellular carcinomas on the lower lip are possible effects of DNA damage on the cell. transcription (16, 17). In those 10% of Werner syndrome patients without a mutation of the Werner gene, mutations in the lamin gene are common (figure 3). Phenotypic similarities between patients with defective Werner helicase and the lamin gene raise the possibility that the gene products interact or are involved in the regulation of the same processes. Fanconi anemia Signs of Fanconi anemia are short stature, skeletal anomalies and pancytopenia with progressive aplastic anemia from the sixth to eighth year of life, and increased risk of malignancy, often acute myeloid leukemia. The haematological symptoms are curable with bone marrow transplantation, but the genomic instability of other cells along with hypersensitivity to DNA attacking agents and increased risk of solid tumors, in particular spinocellular skin cancers, remains (figure 4). Fanconi anemia has a prevalence of 1 : 300 000 and its inheritance pattern is autosomal recessive or X-linked. Twelve complementation groups have been described on the X chromosome. These proteins form the FA protein complex, which has an important role in DNA damage recognition and repair. The molecular functions of the proteins of the FA complex have not been elucidated in detail. Fanconi proteins are probably involved in the repair of DNA double strand breaks and strand cross linkings via cisplatin and other cell cycle modulating agents (18). The basis of genomic instability The genomic stability of DNA is a prerequisite for the functioning of organs and the body as a whole. In evolutionary terms, various pathways have developed for the repair of DNA damage. Even in physiological aging, DNA damage accumulates and as yet poorly understood aging-related signalling pathways are activated. With the help of the progeroid syndromes, the central role of intact DNA repair in genomic stability has been clarified, even for physiological aging. The progeroid syndromes have made evident the connection between increased concentrations of toxic reactive oxygen species and overwhelming of the DNA repair system, as well as with shortened telomeres and replicative senescence. There are numerous examples which suggest that a similar connection applies in physiological aging and in age-related diseases such as osteoporosis, arthritis, atherosclerosis, and neurodegenerative diseases. The following explains the molecular background in brief. Dtsch Arztebl 2007; 104(6): A 346–53 ⏐ www.aerzteblatt.de 8 MEDICINE DIAGRAM 2 Possible effects of DNA damage on the cell Disturbances of nucleotide excision repair Genetic defects of nucleotide excision repair leads to xeroderma pigmentosum, Cockayne syndrome or Trichothiodystrophy. The partially overlapping symptoms in these syndromes are at least partially attributable to similar defects in the proteins involved in the multiprotein complex of nucleotide excision repair. Nevertheless, progeroid syndromes are still distinguishable from one another (table). In order to understand their molecular basis, the following principles of nucleotide excision repair are under discussion . The replication and transcription of DNA can be damaged by ultraviolet light and other genotoxic agents. Even individual lesions in the actively transcribed DNA strand of a gene can block transcription and in the extreme case, lead to cell apoptosis. DNA damage outside an actively transcribing gene seldom poses an acute threat to the cell, but can in the longer term lead to malignant transformation. The most important repair system for DNA damage arising through ultraviolet of oxidative stress is nucleotide excision repair. The two subtypes of the nucleotide excision repair system ensure the repair of DNA damage which leads to disordered helix formation. Transcription-coupled repair mends DNA damage solely in actively transcribing genes. RNA polymerase II, which attaches to the point of damage, and which transcribes DNA into RNA recruits a repair complex involving multiple proteins at the site of the lesion. Damage in the area of the genome which is not actively transcribing is corrected via the global genomic repair. In this system the damage is recognized by the XPC protein complex. Further steps of the repair process are identical between the two subtypes of nucleotide excision repair (diagram 1). The process of transcription-coupled repair and global genomic repair can for the sake of simplicity be reduced to four stages: > Damage recognition and binding of the repair complex > DNA strand separation > Excision of the damage over a length of around 30 molecules using endonucleases > Replacement reaction via DNA polymerases delta and epsilon and DNA reconnection. The process of nucleotide excision is shown graphically in diagram 1. Activation of signalling pathways Non-repaired or incorrectly repaired DNA double strand breaks are, e.g., the cause of ataxia teleangiectasia. The underlying molecular mechanisms and malfunctioning signalling pathways are summarized in a review (19). The effects of non-repaired DNA damage are depicted in diagram 2. Dtsch Arztebl 2007; 104(6): A 346–53 ⏐ www.aerzteblatt.de 9 MEDICINE Future perspectives The elucidation of the progeroid syndromes and the characterization of the molecular signalling pathways aids to the understanding of both the illnesses themselves, and the processes of physiological aging. The recognition of the underlying mechanisms has already been used as part of the development of experimental treatment methods. Endogenous DNA repair after UV exposure has been supported by the use of liposomally encapsulated DNA repair enzymes from bacteriophages or cyanobacteria, used topically. These enzymes were able to repair DNA damage independently of nucleotide excision repair. In a multi centre study of xeroderma pigmentosum patients, the application of these enzymes reduced the incidence of spinocellular carcinomas. In Hutchinson Gilford syndrome, the splicing defect of the lamin gene was able to be repaired, at least in cell culture. These initial results suggest that treatment is possible in principle, and may lead the way to new therapeutic interventions for progeroid syndromes. Acknowledgment We would like to thank our colleagues Dr. hum. biol. Matthias Kohn, Dr. med. Nicolai Treiber und Dr. rer. nat. Meinhard Wlaschek for advice and discussion during the writing of this paper. Conflict of Interest Statement The authors declare no conflicts of interest in the terms of the guidance of the International Committee of Medical Journal Editors. Manuscript dates Manuscript received on 7 September 2004, final version accepted on 24 August 2006. Translated from the original German by Dr. Sandra Goldbeck-Wood. REFERENCES 1. Ganten D, Ruckpaul K, Ruiz-Torres A, eds.: Molekularmedizinische Grundlagen von altersspezifischen Erkrankungen. Berlin: Springer 2004. 2. Gustin JF, Hisama FM, Weissman SM, Hrsg.: Chromosomal instability and aging: basic science and clinical implications. New York: Marcel Dekker 2003. 3. GENE-Reviews: www.genetests.org 4. International Registry of Werner Syndrome: www.wernersyndrome.org 5. Progeria Research Foundation: www.progeriaresearch.org 6. Genetics Home Reference: ghr.nih.gov 7. Martin GM: Genetic modulation of senescent phenotypes in homo sapiens. Cell 2005: 120: 523–32. 8. Kipling D, Davis T, Ostler EL, Faragher RG: What can progeroid syndromes tell us about human aging? Science 2004: 305: 1426–31. 9. Martin GM, Oshima J: Lessons from human progeroid syndromes. Nature 2000: 408: 263–6. 10. Cleaver JE: Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer 2005: 5: 564–73. 11. Hoeijmakers JH: Genome maintenance mechanisms for preventing cancer. Nature 2001: 411: 366–74. 12. Andressoo JO, Hoeijmakers JH: Transcription-coupled repair and premature ageing. Mutat Res 2005: 577: 179–94. 13. Ljungman M, Lane DP: Transcription – guarding the genome by sensing DNA damage. Nat Rev Cancer 2004: 4: 727–37. 14. Hickson ID: RecQ helicases: caretakers of the genome. Nat Rev Cancer 2003: 3: 169–78. 15. Shiloh Y: ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 2003: 3: 155–68. 16. Pollex RL, Hegele RA: Hutchinson Gilford progeria syndrome. Clin Genet 2004: 66: 375–81. 17. Gruenbaum Y, Margalit A, Goldman RD, Shumaker DK, Wilson KL: The nuclear lamina comes of age. Nat Rev Mol Cell Biol 2005: 6: 21–31. 18. Taniguchi D, D`Andrea AD: Molecular pathogenesis of Fanconia anemia: recent progress. Blood 2006: 107: 4223–33. 19. Lombard DA, Chua KF, Mostovslavsky R, Franco S, Gostissa M, Alt FW: DNA repair, genome stability, and aging. Cell 2005; 120: 497–512. Corresponding author Prof. Dr. med. Karin Scharffetter-Kochanek Universitätsklinik für Dermatologie und Allergologie Universitätsklinikum Ulm Maienweg 12, 89081 Ulm, Germany [email protected] Dtsch Arztebl 2007; 104(6): A 346–53 ⏐ www.aerzteblatt.de 10