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At least 19 recordsLinked to original sources
PubMed1991

Reduced DNA repair in progeria cells and effects of gamma-ray irradiation on UV-induced unscheduled DNA synthesis in normal and progeria cells.

A reduction in the amount of UV-induced unscheduled DNA synthesis (UDS), and reduced cell survival and host-cell reactivation against UV exposure in Hutchinson-Gilford progeria syndrome cell strains were shown. UV-induced UDS in 4 progeria cell strains was 33-50% of the normal level. A similar reduction in the UV-induced UDS in normal cells was caused by gamma-ray irradiation to the cells before UV irradiation. The dose of gamma-rays required to cause a reduction in UDS of normal cells to the level of progeria cells was 40 Gy and the reduction was reversible after 2 days. In progeria cells, gamma-ray irradiation further reduced UDS with a lower gamma-ray dose required than in normal cells, and the reduction was also reversible but with less relative recovery than in normal cells. The presence of a 'built-in' defect in progeria cells responsible for the reduced DNA-repair capacity was suggested, and such defect may share a common mechanism with the reduction of UV-induced UDS in normal cells caused by gamma-ray irradiation.

Adolescent↗
PubMed1993

Elevated levels of glycoprotein gp200 in progeria fibroblasts.

The glycosylation of proteins in fibroblasts from people with the premature ageing disease Hutchinson-Gilford Progeria Syndrome (progeria) was investigated. Protein was prepared from fibroblast cell lines established from skin biopsy taken from progeria patients and control donors. Glycoproteins were labelled by the covalent attachment of the steroid hapten digoxygenin to the sugar group. After separation of total protein by SDS-PAGE and electroblotting onto Immobilon-PTM, glycoproteins were detected by enzyme immunoassay. We have observed a glycoprotein of M(r) 200 kDa which is consistently present in protein preparations from progeria fibroblasts and which is absent, or markedly reduced, in preparations from control fibroblasts. This suggests that it may be useful as a marker for progeria. Similar analysis of progeria lymphoblast and control lymphoblast cultures did not show this altered pattern of glycosylated proteins, indicating that it may be cell-type specific. Glycoproteins were also detected by labelling fibroblasts in vitro with D-[6-3H]glucosamine hydrochloride followed by SDS-PAGE of isolated protein and subsequent fluorography. Profiles of glycoproteins from progeria and control fibroblasts were consistent with those obtained from labelling of carbohydrate groups with digoxygenin. Protease digestion of cell protein verified that the band at M(r) 200 kDa contains a protein core. Characteristic features of progeria primarily involve the connective tissue and include wrinkled and loose skin, loss of soft tissue, thin limbs and stiff joints. Death of progeria patients is usually a result of cardiovascular abnormalities. The most consistent manifestations thus involve the connective tissue. The glycoprotein of M(r) 200 kDa which we have observed in progeria fibroblasts in vitro could reflect a perturbation in glycosylation which may underly the connective tissue defects seen in progeria.

Adult↗
PubMed1999

Altered levels of primary antioxidant enzymes in progeria skin fibroblasts.

Free radicals are involved in the aging process. In this study, the profile of primary antioxidant enzymes that scavenge reactive oxygen species (ROS) was examined for the first time in human skin fibroblasts from progeria, a premature aging disease. Altered levels of antioxidant enzymes were found in progeria cells. Basal levels of MnSOD were decreased in progeria cells as well as a blunted induction in response to chronic stress. This change may contribute to the accelerated aging process in progeria cells. In contrast, the levels of CuZnSOD showed no progeria-related change. Two H2O2 removing enzymes demonstrated a significant reduction in progeria cells: only 50% of normal CAT activity and 30% of normal GPX activity can be detected in progeria cells. This diminished H2O2 removing capacity in progeria cells may lead to an imbalance of intracellular ROS and therefore may play an important role in the development of progeria.

Adolescent↗
PubMed1995

Hutchinson-Gilford progeria types defined by differential binding of lectin DSA.

Hutchinson-Gilford Progeria Syndrome (progeria) is an extremely rare childhood disorder characterized by precocious senility which presents features similar to those seen in human aging. We have previously described a consistent increase of the glycoprotein gp200 in progeria skin fibroblasts in vitro. Here we extend these glycosylation studies and present evidence for the existence of two types of progeria skin fibroblasts. These two forms, called D- and D+, are distinguished by their response to the lectin DSA. In the D- group, DSA bound glycoproteins from progeria fibroblast strains AG03513B and AG10750 with markedly lower affinities compared with glycoproteins from three control fibroblast strains. In the D+ group, DSA binding to glycoproteins from four other progeria strains AG01972A, AG06297A, AG06917 and AG03198, was comparable to controls. Discrimination by DSA is the most distinctive feature of the D- and D+ groups, in contrast to binding of lectins Con A, GNA, PHA-L, RCA120, AAA and PNA which show no such selectivity. The data are consistent with a model of altered glycosylation in the D- type of progeria fibroblasts.

Adolescent↗
PubMed1991

Altered response of progeria fibroblasts to epidermal growth factor.

The Hutchinson-Gilford syndrome (progeria) is a rare disorder in childhood characterized by premature and accelerated aging. This study reports the effect of a potent growth factor, EGF, on the proliferative capacities and extracellular matrix macromolecules and collagenase expression of two strains of progeria skin-derived cells. At low population doubling levels (PDL less than 10), confluent cultures of progeria fibroblasts made quiescent by lowering the concentration of serum in the medium did not respond to EGF while the mitotic activity of normal PDL-matched fibroblasts was almost maximally restored upon addition of EGF. No obvious difference between normal and low PDL progeria fibroblasts was observed in the number and in the affinity of the receptors measured by [125I]EGF binding. The synthesis of collagen and non-collagen proteins was similar in normal and affected cells at low and high serum concentration and both types of cells responded to EGF by a specific inhibition of collagen synthesis. Besides a normal level of mRNA coding for type I and type III collagens, collagenase and laminin, progeria fibroblasts expressed a high level of elastin and type IV collagen mRNA. Like normal fibroblasts, progeria cells responded to EGF by a decrease in the level of mRNA for fibrillar collagens and elastin. In contrast, a complete lack of response to EGF was observed for collagenase mRNA whereas the expression of this enzyme was strikingly induced by EGF in normal PDL-matched cells. The abnormal expression of type IV collagen was not significantly modified by EGF. At PDL greater than 10, progeria cells exhibited features of senescence. A significant reduction of collagen synthesis was observed and no further inhibition by EGF was recorded.

Cell Division↗
PubMed1982

[Cellular DNA repair, proliferative activity and biochemical characteristics in the human premature aging syndrome (progeria)].

Fibroblasts of a patient with the Hutchinson-Gilford progeria show a decreased proliferative activity in culture and run through no more than 19 subcultivations. Progeria cells rejoin gamma-induced single strand DNA breaks to the same extent and with the same rate as do normal cells. Spontaneous and induced by X-ray chromosome aberration frequency in progeria cells does not differ from that in normal cells. The activity of DNA-polymerases alpha, beta and gamma in different way depends on culture conditions in progeria and normal cells, but no expressed deficiency of these enzymes was found in progeria cells. The activity of easy-soluble arginine-specific proteases in progeria fibroblasts is sharply decreased, and sensitivity of proteins in these cells to trypsin-catalyzed hydrolysis is significantly increased compared to that of normal cells. Defect in the turnover of intracellular proteins is considered to be a reason of a rapid accumulation of altered proteins in cycling cells and a possible reason of accelerated ageing of progeria cells in vitro.

Cell Division↗
PubMed1993

Audiologic and otolaryngologic findings in progeria: case report.

Progeria is a rare syndrome, with an estimated incidence of 1 per 250,000 births. Although children with progeria have the appearance of premature aging or senility, the term is misleading because reported cases of progeria have not manifested most physical or biochemical aspects of old age. Many children with progeria appear normal at birth and then progressively, and rather rapidly, develop the characteristic features during early childhood. Although first described in the 1880s, only approximately 100 cases of progeria are reported in the international literature. The single case study of hearing in progeria, which appeared in 1965, is limited to pure-tone and speech audiometry findings. We report the results of otolaryngologic examination and pure-tone, speech, immittance, and auditory brainstem response (ABR) audiometry for a 5-year-old female with progeria. The patient had a mild-to-moderate, bilateral, conductive hearing loss. Immittance measurements were consistent with fixation of the ossicular chain and this was confirmed surgically. Mildly prolonged ABR wave I-V latencies suggest possible auditory central nervous system involvement.

Acoustic Impedance Tests↗
PubMed1990

Altered regulation of platelet-derived growth factor A-chain and c-fos gene expression in senescent progeria fibroblasts.

The study of human genetic disorders known as premature aging syndromes may provide insight into the mechanisms of cellular senescence. These diseases are clinically characterized by the premature onset and accelerated progression of numerous features normally associated with human aging. Previous studies have indicated that fibroblasts derived from premature aging syndrome patients have in vitro growth properties similar to senescent fibroblasts from normal individuals. As an initial approach to determine whether gene expression is altered in premature aging syndrome fibroblasts, RNA was prepared from various cell strains and used for gel blot hybridization experiments. Although normal fibroblasts only express platelet-derived growth factor (PDGF) A-chain mRNA for a brief period following mitogenic stimulation, one strain of Hutchinson-Gilford (progeria) syndrome fibroblasts, AG3513, constitutively expresses PDGF A-chain mRNA and PDGF-AA homodimers. The PDGF A-chain gene does not appear to be amplified or rearranged in these fibroblasts. AG3513 progeria fibroblasts have properties characteristic of senescent cells, including an altered morphology and a diminished mitogenic response to growth promoters. The diminished response of AG3513 progeria fibroblasts to PDGF stimulation was examined in some detail. Studies using 125I-PDGF-BB, which binds with high affinity to both A- and B-type PDGF receptors, indicate that normal and AG3513 progeria fibroblasts have a similar number of PDGF receptors. Although receptor autophosphorylation occurs normally in PDGF-stimulated AG3513 progeria fibroblasts, c-fos mRNA induction does not. The senescent phenotype of AG3513 fibroblasts is probably unrelated to their constitutive PDGF A-chain gene expression; further studies are necessary in order to directly address this issue. Also, additional analysis of this progeria fibroblast strain may provide information on the control of mitogen-inducible gene expression in normal cells.

Adolescent↗
PubMed2000

Progeria kidney has abnormal mesangial collagen distribution.

It has been suggested that progeria, a congenital disorder associated with clinical features that resemble premature aging, may be the result of a connective tissue abnormality. Although to date the clinical and pathologic features for 14 autopsied cases of progeria have been reported, details as to the renal changes in progeria are scanty. We investigated the histological features from a male and female with progeria who died aged 11 years and 20 years respectively. In our young male subject there was no glomerulosclerosis, while the kidney from the older subject showed focal renal scarring with focal glomerulosclerosis and associated tubular atrophy. Two small papillary adenomas were present within the renal cortex of the latter subject. In both cases non-sclerotic glomeruli were moderately enlarged with expansion of mesangial matrix. Immunohistochemical detection of collagens showed absence of collagen I and III within the mesangium of non-sclerotic glomeruli, while there was moderate to marked expression of collagen IV, V and VI. Collagen V is thought to be involved in matrix assembly while collagen VI probably has a regulatory role in extracellular matrix development and these are either not seen or are very weakly expressed in normal renal mesangium. The distribution of collagen within the mesangium of progeria kidney is evidence in support of the concept that progeria is a primary connective tissue disorder.

Adult↗
PubMed1995

Hutchinson-Gilford progeria fibroblasts exhibit metabolically normal uridine uptake and RNA synthetic rates.

The accelerated aging disease Hutchinson-Gilford progeria syndrome displays altered messenger RNA levels in cultured fibroblasts, yet little is known of effects on transcription by RNA polymerases other than RNA polymerase II. Total RNA metabolism was examined by incubation of Hutchinson-Gilford progeria fibroblasts with [5-3H]uridine in asynchronous culture. Uptake of radiolabel was quantitative and was incorporated preferentially (99 +/- 0.3%) into newly synthesized RNA. Progeria and control cultures showed comparable rates of uptake of radiolabel, time courses of RNA synthesis, and relative intensity profiles of newly synthesized ribosomal RNA. These characteristics held over a greater than ten-fold range of cell densities (5 x 10(3) to 8 x 10(4) cells/cm2). Progeria and control fibroblasts thus have comparable metabolic capacities for uridine uptake and net RNA production, emphasizing the relative specificity of transcriptional changes previously identified in progeria cells.

Biological Transport↗
PubMed1986

Urinary hyaluronic acid elevation in Hutchinson-Gilford progeria syndrome.

The basic genetic defect in the Hutchinson-Gilford Progeria Syndrome (progeria), a premature aging syndrome, is unknown. To investigate possible defects in hyaluronic acid (HA) metabolism in this disease, the urinary excretion of HA was studied. Urine specimens from 11 patients with this disorder were examined for HA by a novel high performance liquid chromatography (HPLC) technique. In patients with progeria, HA excretion ranged from 169 micrograms HA/g creatinine to 1440 micrograms HA/g creatinine. In normal age-matched controls, HA excreted ranged from 0 to 77 micrograms HA/g creatinine. In all, a mean 17-fold increase in HA excretion was observed in patients with progeria when compared with age-matched normal controls. Total glycosaminoglycan (GAG) excretion was not elevated. Amongst normal controls, a modest age-related increase in HA excretion was observed. These results suggest that urinary HA levels are abnormally elevated in progeria.

Adolescent↗
PubMed1986

Elevation of urinary hyaluronic acid in Werner's syndrome and progeria.

Werner's syndrome and Hutchinson-Gilford progeria syndrome (progeria) are human genetic diseases which may serve as models for the study of premature aging. The basic defects underlying these diseases are unknown. An abnormally high level of urinary hyaluronic acid (HA) excretion has been previously reported in several Werner's and one progeria subject, all from Japan. To determine if a high HA level is a reliable marker for these diseases, we quantitated the urinary excretion of HA in three progeria subjects, one subject with an atypical progeroid syndrome, and a Werner's syndrome subject. Compared to controls, the total urinary HA was found to be markedly increased in the three progeria samples and in the Werner's syndrome sample. These findings support the previous observations indicating elevated HA may be a specific marker for these diseases.

Adolescent↗
PubMed1988

Elevated c-myc expression in progeria fibroblasts.

Protooncogene expression was determined in cultured human fibroblasts derived from donors diagnosed with Hutchinson-Gilford Syndrome (Progeria). An increased level of c-myc expression was noted in progeria cells compared to normal parental controls and unrelated, unaffected, age-matched controls. In two progeria cultures a 150% increase in c-myc expression was observed, while a third progeria culture, subsequently identified as a non-classic progeria showed a 45% increase in c-myc expression. Southern blot analysis did not indicate an amplification or translocation of the c-myc gene. No significant differences were found in the expression of the c-erbB or c-src protooncogenes.

Cells, Cultured↗
PubMed1992

Progeria: a human-disease model of accelerated aging.

Progeria is a rare genetic disease with striking features that resemble accelerated aging. The inheritance pattern, paternal age effect, and lack of consanguinity argue that it is due to a sporadic dominant mutation. We have observed elevated levels of hyaluronic acid (HA) excretion in progeria patients. In several progeria patients we observed normal levels of growth hormone (GH) but very low levels of insulin-like growth factor I along with very high basal metabolic rates (BMRs). A trial of GH treatment was begun, which resulted in a marked increase in linear growth and a paradoxical drop in BMRs in these two patients. We hypothesize that the failure of patients with progeria to thrive may be due to a bioinactive form of GH and a lack of vasculogenesis caused by excess HA. An understanding of the progeria genetic mutation may define a key gene with a major effect on normal aging.

Basal Metabolism↗
PubMed1978

Phenylalanyl synthetase function in cultured fibroblasts from subjects with progeria.

Since progeria cells contain a diversity of altered proteins, some aspects of phenylalanyl synthetase function were examined in semipurified extracts of cultured skin fibroblasts using mixed rabbit tRNA as acceptor. No significant differences were found in the Km and Vmax for phenylalanine or ATP in progeria cells compared with controls. Initial velocities of both progeria and control synthetases were lower at late passage owing to either reduced enzyme content or reduced catalytic efficiency. Reverse phase 5 chromatography of tRNAs acylated by progeria and control synthetases gave a single peak of labeled phenylalanine tRNA in all cases with no secondary peaks evident. Total activity of phenylalanyl synthetase in progeria cells was similar to that of control cells at early passage while late-passage control cells had lower specific activities of these synthetases per unit protein.

Adenosine Triphosphate↗
PubMed1990

Hutchinson-Gilford progeria syndrome in siblings. Report of three new cases.

The Hutchinson-Gilford progeria syndrome is a rare, inherited, pediatric condition with features of premature and accelerated aging. The pattern of inheritance is uncertain though both autosomal dominant and autosomal recessive modes have been proposed. The patients usually present after the 1st year of life with progressive skin and skeletal changes that give rise to a characteristic physical appearance. Three siblings seen at the University of Benin Teaching Hospital are described in this report, the third documenting the occurrence of progeria in African black patients. The two older siblings show the classic physical and radiologic changes described in progeria whereas the third, a 2-year-old boy, manifests only the early physical and radiologic changes of the disease. We compare the radiologic features of progeria with those of other progeroid conditions: acrogeria, Werner's and Cockayne's syndromes.

Child↗