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Hutchinson Gilford Progeria Syndrome

Progeria is an extremely rare genetic condition which causes physical changes that resemble greatly accelerated aging in sufferers. The disease affects around 100 in 48 million newborns. Currently, there are approximately 35 known cases in the world. There is no known cure. Most people with progeria die around 13 years of age. Progeria is of interest to scientists because the disease may reveal clues about factors involved in the process of aging, because it is an "accelerated aging" disease. But unlike most other "accelerated aging diseases" (like Werner's syndrome), progeria is not caused by defective DNA repair. more...

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The condition was first identified in 1886 by Jonathan Hutchinson and Hastings Gilford. The condition was later named Hutchinson-Gilford Progeria syndrome; the name was derived from the Greek for "prematurely old". Around 100 cases have been definitely identified since then.


According to 'recent evidence, Progeria may be a de novo dominant trait. It develops during cell division in a newly conceived child or in the gametes of one of the parents. It is caused by mutations in a LMNA (Lamin A' protein) gene on chromosome 1.


Symptoms generally begin appearing around 18-24 months of age. The condition is distinguished by limited growth, alopecia and a characteristic appearance with small face and jaw and pinched nose. Later the condition causes wrinkled skin, atherosclerosis and cardiovascular problems. Mental development is affected. Individuals with the condition rarely live more than 16 years; the longest recorded life-span was 26 years. The development of symptoms is comparable to aging at a rate six to eight times faster than normal, although certain age-related conditions do not occur.


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role of telomeres in ageing and cancer, The
From British Journal of Biomedical Science, 9/1/98 by Mera, Steven L

Abstract: Telomeres are regions of DNA that cap the ends of linear chromosomes. In somatic cells the telomeres shorten progressively with every cell division, reducing the number of tandem repeat sequences. Eventually the chromosomes become unstable and the cell is no longer able to replicate. This represents an inherent biological clock in which the somatic cell has only a finite capacity for division. In contrast, germ cells do not undergo telomeric shortening and have relatively unlimited capacities for cell division. The difference is that germ cells retain the enzyme telomerase which is able to restore the telomere ends that are lost during cell division. Although telomerase activity is absent in most somatic cells, cancer cells acquire the ability to activate the enzyme, ensuring their immortal growth characteristics and selective advantage over normal somatic cells.

Key words: Cell aging. Neoplasms. Telomerase. Telomere.


In humans, the ends of the chromosomes, known as telomeres, comprise multiple (tandem) repeats of the base sequence TTAGGG. In some cells, these repeats can extend to more than 15 kilobase (kb) pairs. Telomeres play several roles in maintaining the stability of the genome, forming a distinct structure which inhibits fusion, translocation and non-disjunction of chromosomes.' During the replication of DNA, telomeres act as primer sequences for DNA polymerase. This binds to the primer site and synthesises new DNA using the original DNA strand as a template. The primer site on the original DNA can not be read by DNA polymerase because it is already bound; consequently the telomere end is not replicated. This is repeated throughout each cell-cycle so that there is a progressive shortening of the chromosome (Fig. 1). The rate of telomere loss in somatic cells is in the order of 50 to 200 nucleotides per somatic cell division.2'3 Ultimately, so many of the telomere repeats are lost that there are not enough for DNA polymerase to bind on to, and cell replication ceases at this point. This non-dividing state, termed replicative senescence, typically occurs after 60 to 80 doublings in human fetal or neonatal cells.'

It has been known for many years that cultured human cells, such as fibroblasts, have a limited potential for cell division, and, moreover, the number of cell doublings achievable (known as the Hayflick number) decreases as the age of the donor increases. This correlates with telomere length in cultured human somatic cells, which also decreases as donor age increases. In contrast, telomeres in germ cells do not undergo the progressive shortening that is characteristic of somatic cells, and this confers a relatively unlimited capacity for germ-cell replication.s This property is achieved through the presence of telomerase, an enzyme-RNA complex present in germ cells, but absent in somatic cells (Fig. 2). Other normal human cells which retain telomerase activity are various stem cells, including haemopoietic cells, although these telomerase-competent cells undergo slowly progressive telomere shortening with age.6

Telomeres and telomerase

The role of telomerase is to restore unreplicated telomere sequences to the ends of newly synthesised DNA. The RNA component of the complex contains a binding domain that allows it to bind to the 3'terminus of the DNA primer. It also contains a templating domain which specifies the addition of the appropriate telomere deoxynucleotides. A proposed mechanism7 for correcting unreplicated telomeres starts by extending the 3'-terminal end of the primer strand with newly synthesised telomeric repeat sequences encoded by telomerase RNA. This synthesis is reminiscent of the activity of reverse transcriptases such as those carried by retroviruses and transposons (mobile genetic elements which can be replicated and inserted into new locations in the genome). The extended portion of the strand then acts as a binding domain for DNA polymerase, which synthesises new polynucleotide in the 5' to 3' direction, thereby filling the unreplicated gap in the newly synthesising DNA strand (Fig. 3).

Telomeres and ageing

Much of our current understanding of the biology of telomeres stems from the observations that telomeres are shorter in somatic cells compared to germ cells (about 9 kb of TTAGGG repeats in human sperm compared with 4 kb in somatic cells2), and that telomeres in somatic cells from older people are shorter than those found in younger individuals.' In addition, children who have inherited the so-called premature ageing syndrome (Hutchinson-Gilford progeria) have shorter telomere lengths in their DNA than agematched controls. Other genetic ageing syndromes such as Werner's syndrome and Down's syndrome are associated with accelerated loss of telomeres, although the early departure of cultured cells from the cell-cycle may, in these cases, be due to other mechanisms.9 It is a general feature of tissues and organs throughout the body that ageing is accompanied by a loss in cell numbers, and this loss contributes to senescence." There are, however, some discrepancies in the argument that telomere shortening is the sole mechanism for the regulation of cellular lifespan. Most notably, some inbred mouse strains have telomeres that are several times longer than those in humans, but these animals have much shorter lifespans than humans, and the cultured mouse cells do not survive longer in culture."

Interestingly, a study of young bone-marrow transplant recipients showed that telomeres in the transplants became much shorter compared with those in donors of the bone marrow. The average telomere loss was about 0.4 kb, equivalent to a median of 15 years ageing in healthy controls. It is suggested that the accelerated loss is caused by additional stress imposed on the cells during the grafting process, equivalent to a pronounced ageing effect. This may contribute to the increased incidence of haemopoietic disorders in bone-marrow transplant recipients commonly seen in later life.6'2

Recently, more definitive evidence for the crucial role of telomeres in the replicative senescence of human cells has become available. Normally, when cells lose their telomerase activity they retain the template RNA component of the enzyme complex, and only the reverse transcriptase enzyme is missing. It is now possible to restore telomerase activity to normal human somatic cells by transfecting them with a gene for the reverse transcriptase sub-unit of telomerase.3 This results in the addition of TTAGGG repeats to the telomere ends, and an extension of the normal lifespan by at least 20 doublings. Moreover, the telomere-extended cells retain a normal karyotype and, compared with nonextended controls, show reduced staining for p-galactosidase, a marker for cellular senescence. Similar results were found in different cell types, including retinal pigment epithelial cells, foreskin fibroblasts and vascular endothelial cells, demonstrating that telomere shortening is probably a universal phenomenon in the senescence of human cells. Although this represents an intrinsic timing system for the ageing process, it is also likely that telomere shortening represents a tumour suppressor system, ensuring that genetically damaged cells which escape other control mechanisms (apoptosis, for example) are ultimately terminated. While in vitro experimental telomere lengthening offers prospects for the in vivo alteration of cells susceptible to age-related damage and senescence, such as skin atrophy, macular degeneration and even atherosclerosis changes, there are concerns that such lifespan extension could confer, or predispose to, a malignant phenotype.

Telomeres and cancer

Both germ cells and cancer cells share the capacity for infinite cell division. In germ cells, this property is achieved by telomerase activity, and, likewise, it has been shown that most immortal cancer cells display telomerase activity.'4 In some cancers there is a correlation between telomerase expression, differentiation stage and prognosis.5 Cells from benign tumours, such as leiomyoma (uterine fibroid), generally do not possess telomerase activity. Unfortunately, the picture is not entirely clear-cut and there are instances in which cancer cells do not express telomerase (paediatric gliomas),'6 and examples of neoplastic' and non-neoplastic proliferative processes in which cells possess telomerase activity. None the less, the common association of telomerase with malignancy (present in about 85% of tumours) presents the possibility of a new target for cancer treatment. Theoretically, telomerase inhibitors could be used to arrest cancer cell growth while having very little effect on normal cells because of their absence of telomerase. The development of such drugs is now being actively pursued by the Geron Corporation in California, USA.7

Notwithstanding the formidable technical difficulties in developing new drugs and getting them through clinical trials and approvals processes, there are some concerns that cancer cells may be able to evade such controls to their growth. This stems from observations in mice which show that some tumours retain long telomeres and yet have no detectable telomerase activity, suggesting that the cells have invoked an alternative mechanism for maintaining telomere length.'8 Currently, research is underway to elucidate these alternative mechanisms for maintaining telomere length.


Blackburn EH. Structure and function of telomeres. Nature 1991; 350:569-73.

Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature 1990; 345:458-60. Allsopp RC, Vaziri H, Patterson C et al. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA 1992; 89:10114-18.

Campisi J. The biology of replicative senescence. Eur J Cancer 1997; 33:703-9.

Kim NW, Piatyszek MA, Prowse KR et al. Specific association of human telomerase activity with immortal cells and cancer. Science 1994; 266:2011-15.

6 Wynn RF, Cross MA, Hatton C et al Accelerated telomere shortening in young recipients of allogeneic bone-marrow transplants. Lancet 1998; 351:178-81.

7 Morin GB. The implications of telomerase biochemistry for human disease. Cancer 1997; 33:750-60. 8 Hastie MD, Dempster M, Dunlop MG et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 1990; 346:86S8.

9 Schulz VP, Zakian V, Ogburn CE et al. Accelerated loss of telomeric repeats may not explain accelerated decline of Werner's syndrome cells. Ilum Genet 1996; 97: 7504. 10 Mera SL. The biological basis of ageing. In: Understanding disease: pathology and prevention. Cheltenham: Stanley Thornes, 1997: 263-83.

11 Kipling D, Cooke HJ. Hypervariable ultra-long telomeres in mice. Nature 1990; 347:400-2.

12 Shay JW. Accelerated telomere shortening in bone-marrow

recipients. Lancet 1998; 351:153-4.

13 Bodnar AG, Ouellette MI, Frolkis M et al. Extension of lifespan by introduction of telomerase into normal human cells. Science 1998; 279:349-52.

14 Shay JW, Bacchetti S. A survey of telomerase activity in human cancer. Eury Cancer 1997; 33:787-91. 15 Kim NW. Clinical implications of telomerase in cancer. Eur_

Cancer 1997; 33:781-6.

16 DeMasters BKK, Markham N, Lillehei KO et al. Differential telomerase expression in human primary intracranial tumours. Am T Clin Pathol 1997; 107:548-54.

17 Lundblad V, Wright WE. Telomeres and telomerase: a simple picture becomes complex. Cell 1996; 87:369-73. 18 Bryan TM, Englezou A, Dalla-Pozza L et al. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nature Med 1997; 3:1271-4.


Faculty of Health and Environment, Leeds Metropolitan University, Calverley Street, Leeds LS1 311E, England, UK

(Accepted 18 May 1998)

Copyright Royal Society of Medicine Press Ltd. Sep 1998
Provided by ProQuest Information and Learning Company. All rights Reserved

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