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PubMed2006

DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A.

The genetic diseases Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) arise from accumulation of farnesylated prelamin A because of defects in the lamin A maturation pathway. Both of these diseases exhibit symptoms that can be viewed as accelerated aging. The mechanism by which accumulation of farnesylated prelamin A leads to these accelerated aging phenotypes is not understood. Here we present evidence that in HGPS and RD fibroblasts, DNA damage checkpoints are persistently activated because of the compromise in genomic integrity. Inactivation of checkpoint kinases Ataxia-telangiectasia-mutated (ATM) and ATR (ATM- and Rad3-related) in these patient cells can partially overcome their early replication arrest. Treatment of patient cells with a protein farnesyltransferase inhibitor (FTI) did not result in reduction of DNA double-strand breaks and damage checkpoint signaling, although the treatment significantly reversed the aberrant shape of their nuclei. This suggests that DNA damage accumulation and aberrant nuclear morphology are independent phenotypes arising from prelamin A accumulation in these progeroid syndromes. Since DNA damage accumulation is an important contributor to the symptoms of HGPS, our results call into question the possibility of treatment of HGPS with FTIs alone.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1976

[Nature of diverse molecular diseases in man].

The article comprises the literature data on a new group of enzymopathies in man associated with the defect of the cell reparative mechanisms, which in the norm restore damages of DNA induced by factors of a different character. Special attention is paid to molecular processes observed in the hereditary disease in man--xeroderma characterized by a high sensitivity of the patient to ultraviolet irradiation and by a high incidence of cancer of the skin. Experimental evidences are presented testifying to an elevated sensitivity of cells of such patients to carcinogens, some viruses, and illustrating peculiar features of formation of structural mutations of chromosomes induced by physical, chemical and biological agents. Defects of individual enzymes of reparation in progeria, Fanconi's anemia and some other human diseases are described. The author recommends to simulate defects of reparative enzymes on diploid human cells infected with the virus of leukemia.

Anemia, Aplastic↗
PubMed1975

Human diseases with genetically altered DNA repair processes.

DNA repair of single-strand breaks (produced by ionizing radiation) and of base damage (produced by ultraviolet (UV) light) are two repair mechanisms that most mammalian cells possess. Genetic defects in these repair mechanisms are exemplified by cells from the human premature-aging disease, progeria, which fail to rejoin single-strand breaks, and the skin disease, xeroderma pigmentosum (XP), which exhibits high actinic carcinogenesis and involves failure to repair base damage. In terms of the response of XP cells, many chemical carcinogens can be classified as either X-ray-like (i.e., they cause damage that XP cells can repair) or UV-like (i.e., they cause damage that XP cells cannot repair). The first group contains some of the more strongly carcinogenic chemicals (e.g., alkylating agents). XP occurs in at least two clinical forms, and somatic cell hybridization indicates at least three complementation groups. In order to identify cell lines from various different laboratories unambiguously, a modified nomenclature of XP lines is proposed.

Carcinogens↗
PubMed1999

Progeroid syndrome with facial teleangiectatic erythema, posterior subcapsular cataracts, calcification of basal ganglia and atrium septum defect type 2.

In this report we present the long-term follow-up findings in a young female born to consanguineous parents with the unique association of (1) a progeroid syndrome, (2) facial dysmorphism with relative microcephaly, triangular face, retrognathism and skin erythema, (3) bilateral posterior cataracts, (4) basal ganglia calcifications and (5) atrium septum defect type 2. Intelligence is borderline. Clinical evolution after normal puberty was positive with regression of the facial erythematous changes. Over the years differential diagnosis included progeria, hypohidrotic ectodermal dysplasia, Rothmund-Thompson syndrome, Cockayne syndrome, Bloom syndrome, but the clinical spectrum of abnormalities and the evolution with age were not compatible with one of these diagnoses. Parental consanguinity is in favour of autosomal recessive inheritance.

Abnormalities, Multiple↗
PubMed1976

[Morphology of the cells in the peritoneal exsudate and phosphatase activity of the peritoneal macrophages experimentally aged rats treated with the intracellular bacterium Brucella abortus 19 (author's transl)].

The authors study the morphology of the cells in the peritoneal exsudate and the phosphatase activity of the peritoneal macrophages, obtained from rats with Selye's Progeria-like syndrome. Judging by their morphologic characteristics the macrophages of the experimentally aged rats, before and after contact with Brucella abortus 19 do not differ from those obtained from the unsubjected to experimental ageing rats. The acid phosphatase activity and the adenosinetriphosphatase activity of the macrophages prior to contact with Brucella abortus 19 are nearly identical for both groups of animals. Following contact the activity of the enzymes increases but this increase is slower by aged rats and reaches its maximum 1--2 days later.

Acid Phosphatase↗
PubMed1992

[Hutchinson-Gilford syndrome].

A case report on a 6-year-old boy suffering from the extremely rare Hutchinson-Gilford syndrome (progeria) is presented. The results of histopathological and immunohistological examination of the scar-like skin lesions are reported. Subcutaneous amorphous nodules were eosinophilic, PAS- und elastica-negative und remained unstained with antibodies against collagen type IV, vimentin, and collagenase. The dense perivascular infiltration consisted of CD4+, CD8-, alpha-1-antichymotrypsin-, MAC 387-, and some vimentin-positive cells. Perinodular blood vessels were more abundant and had a thickened wall. Collagen bundles were swollen. The epidermis appeared atrophic with focal basal cell degeneration.

Adipose Tissue↗
PubMed1991

Lethal progeroid syndrome with osteolysis. Case report.

A particular progeroid syndrome with severe acro-osteolysis, cutaneous changes, failure to thrive, and early death is described in a young boy. Progeria and mandibulo-acral dysplasia are discussed, but early death is unusual in these two syndromes. This observation raises the question of a large spectrum including all of these syndromes.

Humans↗
PubMed1990

Sister chromatid exchanges and inhibition of DNA synthesis in irradiated human cells.

X-ray irradiation inhibits DNA synthesis and enhances the frequency of sister chromatid exchanges (SCE) in normal human lymphocytes. On the contrary, cells from patients with Down's syndrome, Xeroderma pigmentosum (form II) and progeria, characterized by radioresistant DNA synthesis, do not show such an increase in SCE frequency. We suggest that radiation-induced SCE frequency is a result of inhibition of DNA replication, rather than a direct damage of chromosomes by ionizing radiation. It is in agreement with Painter's /13/ hypothesis according to which SCE are formed due to asynchronous completion of replication in contiguous replicon clusters. So, probability of SCE formation is the more the lower is rate of replication. Thus, the extent of radiation damage cannot be measured directly by the SCE frequency.

DNA↗
PubMed1990

[Grotton's acrogeria with bone involvement].

A 13-year-old girl had a bird-like face, deficiency of the subcutaneous fatty tissue, dry, thin, transparent and wrinkled skin, especially on the hands and feet, prominent veins and telangiectasia and mottled hyper-pigmentation. X-ray studies revealed acro-osteolysis of the hands and feet. The clinical features corresponded well with Gottron-type acrogeria. The clinical symptoms of premature ageing syndromes, such as progeria, lipodystrophia totalis, Cockayne syndrome, metageria and acrogeria are summarized briefly and compared with the clinical picture observed in our patient.

Adolescent↗
PubMed1985

The cell biology of aging.

It is only within the past ten years that biogerontology has become attractive to a sufficient number of biologists so that the field can be regarded as a seriously studied discipline. Cytogerontology, or the study of aging at the cellular level, had its genesis about 20 years ago when the dogma that maintained that cultured normal cells could replicate forever was overturned. Normal human and animal cells have a finite capacity to replicate and function whether they are cultured in vitro or transplanted as grafts in vivo. This phenomenon has been interpreted to be aging at the cellular level. Only abnormal somatic cells are capable of immortality. In recent years it has been found that the number of population doublings of which cultured normal cells are capable is inversely proportional to donor age. There is also good evidence that the number of population doublings of cultured normal fibroblasts is directly proportional to the maximum lifespan of ten species that have been studied. Cultures prepared from patients with accelerated aging syndromes (progeria and Werner's syndrome) undergo far fewer doublings than do those of age-matched controls. The normal human fibroblast cell strain WI-38 was established in 1962 from fetal lung, and several hundred ampules of these cells were frozen in liquid nitrogen at that time. These ampules have been reconstituted periodically and shown to be capable of replication. This represents the longest period of time that a normal human cell has ever been frozen. Normal human fetal cell strains such as WI-38 have the capacity to double only about 50 times. If cultures are frozen at various population doublings, the number of doublings remaining after reconstitution is equal to 50 minus the number of doublings that occurred prior to freezing. The memory of the cells has been found to be accurate after 23 years of preservation in liquid nitrogen. Normal human cells incur many physiologic decrements that herald the approach of their failure to divide. Many of these functional decrements are identical to decrements found in humans as they age. Thus it is likely that these decrements are also the precursors of age changes in vivo. The finite replicative capacity of normal cells is never seen to occur in vivo because aging and death of the individual occurs well before the doubling limit is reached.

Aging↗
PubMed1976

[Immunocytogenesis and formation of antibodies in experimentally aged animals (author's transl)].

The authors use white rats with experimentally induced Progeria-like syndrome of Selye. The immunologic response following inoculation with the extracellular microbe-parasite D, pneumoniae and the intracellular parasite Br. abortus 19 is studied serologically, cellularly and biochemically. The experimentally aged rats show diminished and retarded plasmocyte reaction and weaker and slower agglutinine synthesis as compared with the controls. The immunochemical analysis of the serums of the experimentally aged rats reveals changes in the serum fractions and an affected ratio of albumin/globulin. The data suggest a disturbed adaptation and a reversal to an older ontogenic form of the aged organism.

Aging↗
PubMed1977

[An case of acute diffuse seleroderma in an infant].

The authors report a case of diffuse scleroderma in a 15 months old infant. Dermatologic (clinical and pathological) findings are quite typical of the disease. On the other hand, in this case some particularities were observed: the age of the infant (second published case beginning before the age of two); the presence of a durable eosinophilia, the absence of visceral lesions and of biological abnormaliteis (of auto-immune nature specially), the evolution towards athrepsica and death within one year. Thus, because of these particularities, the diagnosis of scleroderma remains questionable and the diagnosis of progeria has been considered. The affection appeared in the course of a hepatitis leaving a hepatic fibrosis without inflammatory signs; no conclusion can be drawn about the relations between the hepatic affection and the fatal dermatologic disease.

Acute Disease↗
PubMed1981

Premature aging syndromes affecting the skin.

Consideration of the above syndromes from a dermatologic perspective leads to several conclusions: 1) The "normal changes" associated with aging of the skin have been inadequately defined to date. 2) Although all the premature aging syndromes manifest certain features suggestive of accelerated aging, none closely mimics the normal aging process. The distribution, specific character, and developmental sequence of pathologic findings diverge from those of normal aging for most organ systems in each syndrome. Furthermore, in each disorder many of the accepted features of normal aging are lacking. These discrepancies are at least as pronounced in the skin as in the other involved organ systems. 3) Most of the premature aging syndromes are transmitted by autosomal recessive genes, yet have multiple features that are difficult or impossible to attribute to a single defective enzyme or other protein structure. This suggests that the syndromes may be due to errors in the regulation of various metabolic pathways and argues in favor of an explicit genetic program for aging. 4) The frequency and variety of cutaneous abnormalities in these complex syndromes emphasize the integral relationship of the skin to the rest of the body and the potential value of the skin as a tissue source for studies of underlying disease mechanisms. 5) The relatively recent application of tissue culture technology to the study of progeria, Werner syndrome, and the other premature aging syndromes has already yielded considerable data, offering the hope that our understanding of these diseases may increase rapidly in the coming decades.

Adult↗
PubMed1984

[Incomplete Hutchinson-Gilford syndrome. A patient followed to age 29].

A case is described with incomplete syndrome of Hutchinson-Gilford in a male, aged 29. The development of the disease in the patient was followed-up. The pathologoanatomical changes, observed in the patient were described. Resulting from a severe fibrocalcinosis of the mitral and aortic valves, a congestive cardiac insufficiency developed that led to death at the age of 16. It is stressed that is the "longest" lived patients with progeria, the causes for that being discussed. Some problems of the pathogenesis of the syndrome are also discussed.

Adrenal Insufficiency↗
PubMed1983

[Premature aging syndromes with special reference to lipodystrophy (a case report)].

The authors survey the modern classification of progeria and report on a 12-year old girl suffering from lipodystrophia totalis and diabetes mellitus (Lawrence-Seip-syndrome). The girl developed sclerodermiform changes at the age of one year, at her 10th year acanthosis nigricans, xanthoma tuberosum Fredrickson hyperlipoproteinaemie IV, later II/B type and finally at an age of 11 1/2 year diabetes mellitus.

Child↗
PubMed1980

X-ray sensitivity of fifty-three human diploid fibroblast cell strains from patients with characterized genetic disorders.

The in vitro response of 53 human diploid fibroblast strains to X-irradiation was studied using a clonogenic survival assay. The strains, derived from patients with a variety of characterized clinical conditions, most with a genetic component, ranged in Do (a measure of the slope of the survival curve) from 43 to 168 rads. The mean Do's of six strains from normal individuals was 140 to 152 rads, with an overall range, based on the extremes of their standard errors, of 128 to 164 rads. Three-quarters of the strains studied fell within this range. Strains identified as sensitive came from patients with ataxia telangiectasia, progeria, the two genetic forms of retinoblastoma, and partial trisomy of chromosome 13. No marked radiosensitivity was found among strains derived from patients with a number of other conditions associated with a predisposition to malignancy.

Adolescent↗
PubMed1976

[Cellular immunity against bacteria (intracellular and extracellular parasites) in experimentally aged rats (author's transl)].

The authors study the activity of RES in rats with Progeria-like syndrome of Selye, at the occasion of a repeated infection with bacteria--intracellular parasites (Brucella abortus 19) and bacteria--extracellular parasites (Diplococcus pneumoniae). They establish that immunization improves the activity of RES of the experimentally aged rats; still, its phagocytic and digestive functions remain by far feebler than those of the rats unsubjected to experimental ageing. By the aged animals the RES insufficiency is more pronounced towards the intracellular bacterium Brucella abortus 19, than towards the extracellular Diplococcus pneumoniae.

Aging↗
PubMed1976

[Resistance against intra- and extracellular bacteria in experimentally aged rats (author's transl)].

The authors study the cellular activity of RES against the microbes intracellular and extracellular parasites in rats with pronounced Progeria-like syndrome of Selye. RES of the experimentally aged animals copes, through with a certain delay, with the invading extracellular bacterium Diplococcus pneumoniae, but is utterly helpless against the intracellular microbe Br. abortus 19. These relations are completly inverted in the rats that have not been experimentally aged.

Acid Phosphatase↗