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PubMedDate not supplied

Proteomic analysis of the genetic premature aging disease Hutchinson Gilford progeria syndrome reveals differential protein expression and glycosylation.

Proteomics has revealed differential protein expression and glycosylation in membrane proteins from premature aging Hutchinson-Gilford progeria syndrome fibroblasts (progeria). Progeria is a rare autosomal dominant genetic disorder of premature aging characterized by marked growth retardation and specific, progressive, premature senescent changes of the skin and other tissues. Affected children live to an average age of 13 years. The 1q20-24 region of chromosome 1 which codes for one of these proteins, lamin A/C, has previously been implicated by Brown et al. (1990) who described identical twins with progeria, where cytogenetic analysis showed an inverted insertion in the long arm of the chromosome in 70% of cells. Luengo et al. (2002) similarly reported an interstitial deletion of chromosome 1q23, in a 9-year-old patient with a classic clinical picture of progeria.

Aging, Premature↗
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↗
PubMed2006

Hutchinson-Gilford progeria syndrome: review of the phenotype.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare but well known entity characterized by extreme short stature, low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features that resemble aged persons. Cardiovascular compromise leads to early demise. Cognitive development is normal. Data on 10 of our own cases and 132 cases from literature are presented. The incidence in the last century in the Netherlands was 1:4,000,000. Sex ratio was 1.2:1. Main first symptoms were failure to thrive (55%), hair loss (40%), skin problems (28%), and lipodystrophy (20%). Mean age at diagnosis was 2.9 years. Growth in weight was more disturbed than growth in height, and growth delay started already prenatally. Mean height > 13 years was 109.0 cm, mean weight was 14.5 kg. Osteolysis was wide-spread but not expressed, except in the viscerocranium, and remained limited to membranous formed bone. Lipodystrophy is generalized, only intra-abdominal fat depositions remain present. Cardiovascular problems are extremely variable, both in age of onset and nature. Stroke and coronary dysfunctioning are most frequent. Pathologic findings in coronaries and aorta resemble sometimes the findings in elderly persons, but can also be much more limited. Loss of smooth muscle cells seems the most important finding. Mean age of demise was 12.6 years. Patients can be subdivided in patients with classical HGPS, which follows an autosomal dominant pattern of inheritance, (almost) all cases representing spontaneous mutations, and in non-classical progeria, in whom growth can be less retarded, scalp hair remains present for a longer time, lipodystrophy is more slowly progressive, osteolysis is more expressed except in the face, and survival well into adulthood is not uncommon. Pattern of inheritance of non-classical progeria is most probably autosomal recessive. The cause of HGPS is an abnormally formed Lamin A, either directly by a mutated LMNA gene, or through abnormal posttranslational processing (ZMPSTE24 gene mutations). Of 34 LMNA mutations found in progeria patients, there were 26 classical p.G608G mutations (76%). Pathogenesis is most likely to follow several different pathways. Potential therapeutic strategies are developed along these lines and include RNA interference techniques and inhibition of the dominant-negative influence of abnormally formed Lamin A on polymerization with normally formed Lamin A.

Abnormalities, Multiple↗
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↗
PubMedDate not supplied

Reduced DNA-repair capacity in cells originating from a progeria patient.

A Chinese boy was identified to be suffering from progeria (Hutchinson-Gilford syndrome), the first case of the disease ever reported in China. Cells originating from the patient had a reduced amount of unscheduled DNA synthesis after irradiation with ultraviolet light (UV). The fractions of the progeria cells surviving against UV irradiation measured by colony-forming ability, and the host-cell reactivation capacity of the progeria cells, measured by the plaque formation of UV-irradiated herpes simplex virus were lower than those measured in normal cells. The progeria cells appear to have a reduced capacity to repair UV excision damage.

Cells, Cultured↗
PubMed2006

A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria.

Progerias are rare genetic diseases characterized by premature aging. Several progeroid disorders are caused by mutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural scaffolding for the cell nucleus. In progeria, the accumulation of farnesyl-prelamin A disrupts this scaffolding, leading to misshapen nuclei. Previous studies have shown that farnesyltransferase inhibitors (FTIs) reverse this cellular abnormality. We tested the efficacy of an FTI (ABT-100) in Zmpste24-deficient mice, a mouse model of progeria. The FTI-treated mice exhibited improved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age. These results suggest that FTIs may have beneficial effects in humans with progeria.

Animals↗
PubMed2000

Human aging and progeria.

The notion that all aging is ultimately cell aging is a novel hypothesis and one with growing support. Recent studies in genetics and cell biology are consistent with this view. Criticism of the model is largely reflective of inadequate understanding of both the model itself and human pathology. Hutchinson-Gilford progeria is a segmental progeria that may well be an 'epigenetic mosaic' disease in which certain cell lines exhibit early cell senescence, while others are spared. The general cell senescence model of aging offers a consistent and elegant explanation of both human aging and progeria. More importantly, the model is not only testable but implies fundamental, novel and promising therapeutic avenues for both progeria and more typical age-related diseases.

Aging↗
PubMed1998

Hutchinson-Gilford progeria: faithful DNA maintenance, inheritance and allelic transcription of beta(1-4) galactosyltransferase.

Hutchinson-Gilford progeria syndrome (HGPS) is a fatal segmental aging disorder affecting children. There is a paucity of prior data at the nucleotide level on DNA maintenance in HGPS. We have examined the specific nucleotide sequences and production of allelic transcripts from the locus GGTB2 encoding beta(1-4) galactosyltransferase. Quantitative Northern blots of mRNA from HGPS and control fibroblasts indicated identical mature beta(1-4) galactosyltransferase transcript sizes and amounts, regardless of their altered glycosylation status. DNA sequencing of cDNA derived from HGPS beta(1-4) galactosyltransferase mRNA populations confirmed the encoded amino acid sequence was unaffected. Population studies of 41 unrelated individuals provided allelic frequency estimates for a novel FokI polymorphism, which was identified in two of six progeria cell strains. The polymorphism was faithfully inherited in a progeria pedigree in a Mendelian manner. Furthermore, the polymorphism provided direct evidence through sequencing of reverse transcription polymerase chain reaction products that both alleles were transcribed and generated mature mRNA. Any defects in transcripts were below detectable levels over the lengths of coding sequences examined, despite multiple replication events from conception leading to the production and maintenance of patient-derived cells. These results indicate faithful transcription in HGPS.

Alleles↗
PubMed1980

Detection of HLA antigens on progeria syndrome fibroblasts.

It has been suggested that cultured skin fibroblasts derived from patients with progeria, a premature aging syndrome, have absent or markedly reduced HLA antigen expression, thus implicating a possible immunological role in the pathogenesis of this disease. An analysis of HLA expression in nine progeric fibroblast strains and related familial strains is reported. Normal HLA expression and inheritance were found. No significant association between HLA type and progeria was detected. Therefore, we conclude an abnormality of HLA expression is unlikely to be an underlying defect in progeria.

Cells, Cultured↗
PubMed2004

Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder that causes premature, rapid aging shortly after birth. Recently, de novo point mutations in the Lmna gene have been found in individuals with HGPS. Lmna encodes lamin A and C, the A-type lamins, which are an important structural component of the nuclear envelope. The most common HGPS mutation is located at codon 608 (G608G). This mutation creates a cryptic splice site within exon 11, which deletes a proteolytic cleavage site within the expressed mutant lamin A. Incomplete processing of prelamin A results in nuclear lamina abnormalities that can be observed in immunofluorescent studies of HGPS cells. Mouse models, such as Lmna knockout, Zmpste24 knockout, and Lmna L530P knockin will help the study of progeria. Lmna mutations have also recently been found in patients with atypical forms of progeria. The discovery of the HGPS mutations brings the total number of diseases caused by mutant Lmna to nine, underscoring the astonishing spectrum of laminopathies. Future research into HGPS could also provide important clues about the general process of aging and aging-related diseases.

Aging↗
PubMed1984

Progeria with cardiac hypertrophy and review of 12 autopsy cases in the literature.

An autopsy of an 11 years 5 months old boy with progeria is presented. Hyaluronuria, low growth rate of skin fibroblasts, decreased number of T-cells in lymphocyte subpopulation, increase of anti DNA antibody, and antibody for microsome of thyroid gland were detected clinically. He had suffered an attack of cerebral infarct and died of congestive cardiac failure. Pathologic findings were scleroderma-like skin atrophy, moderate arteriosclerosis of the aorta and great arteries, severely narrowed coronary sclerosis with an extensive subendocardial fibrosis, a large left cerebral infarct with pin-holed stenosis of both internal carotid arteries, cortical atrophy of thymus, and atrophic lymph nodes. The cardiac muscle fibers were slightly hypertrophied and measured 15.5 +/- 2.8 microns in diameter. Histologic findings suggest that increasing of collagen in the connective tissue may play an important role in progeria. Further study of metabolic disturbance in the connective tissue of progeria is necessary.

Autopsy↗
PubMed1976

Progeria: autopsy report of one case, with a review of pathologic findings reported in the literature.

An autopsy case of progeria associated with elastotic degeneration of the skin and preservation of the scalp hair, in a 20-year-old woman, is presented. The pathologic findings were scleroderma-like skin atrophy, elastotic degeneration of the skin, arteriosclerosis, atrophy of the endocrine glands, and acute peritonitis after appendectomy. In the reported cases of progeria, as in Werner's syndrome, no responsible parenchymatous organ has been identified. Rather, connective tissue, widely distributed throughout the entire body, may play an important role. The possible abnormal metabolism of connective tissue in progeria deserves further study.

Adult↗
PubMed2001

Progressive intracranial vascular disease with strokes and seizures in a boy with progeria.

Progeria, a rare genetic disorder, is characterized by severe growth failure, premature aging, and very early atherosclerosis with coronary artery and cerebrovascular disease. There has been no detailed description of progressive cerebrovascular changes in progeria or any attempted neurologic correlation of those changes. A 5-year-old boy developed signs of progeria at 4 months and hypertension at 4 years, treated with atenolol and dipyridamole. Left-sided seizures with a left hemiparesis occurred at 5 years. Magnetic resonance imaging (MRI) showed bilateral acute, subacute, and chronic cerebral infarctions. Magnetic resonance angiography disclosed severe stenosis of the left internal carotid artery. The child was also found to have an aortic valve vegetation and was anticoagulated. He subsequently developed right-sided seizures, and treatment with gabapentin was started. Later, severe stenosis also of the right internal carotid artery was found. MRI showed new left cerebral infarction. The child's neurologic symptoms almost certainly were caused by cerebral infarctions from progressive atherosclerosis of major intracranial vessels, but clinical-neuroradiologic correlations were imprecise. There were multiple cerebral infarctions of different ages, some asymptomatic, others ipsilateral to the child's neurologic findings. No therapy has halted progression of the child's cerebrovascular disease.

Brain↗
PubMed1988

The musculoskeletal manifestations of progeria. A literature review.

Although a superficial similarity exists between the musculoskeletal disorders associated with natural aging and those of progeria, an in-depth analysis reveals profound differences in the pathophysiology between the two processes. The protean manifestations of progeria can best be explained on the basis of the vascular changes found at autopsy. A disorder of the vascular endothelium may predispose progeric vessels to atherosclerotic changes. The unique musculoskeletal manifestations of progeria arise from the effects of premature atherosclerosis on the vascularized connective tissues.

Bone and Bones↗
PubMed2005

[Could progeria be a model for the natural process of aging?].

Acceleration of ageing of urban populations causes the urgent need to carry out research in this area. One of the proposed models of investigation may be progeria. The most frequent syndromes of progeria and the way they are inherited were described. Molecular mechanisms which have essential influence on premature ageing in progeria were discussed. Moreover, their analogies with natural biological process were presented.

Aging↗
PubMed1990

[A case of progeria syndrome with cerebral infarction].

Cerebrovascular involvement is rare in progeria syndrome (Hutchinson-Gilford syndrome). A patient with progeria syndrome, who developed cerebral infarction, was reported. At 7 years of age, she suffered from right hemiplegia and transient ischemic attacks. X-ray CT showed multiple low density lesions in left frontal and parieto-occipital areas, which were enhanced with a contrast medium. Cerebral angiography demonstrated complete occlusion of left carotid artery and narrowing of vertebral artery. Brain imaging using 123I-N-isopropyl-p-iodoamphetamine (123I-IMP SPECT), which expressed regional cerebral blood flow, showed extensive perfusion defect over the left cerebral hemisphere in early scans, and redistribution phenomena in late scans. The symptoms improved gradually, which correlated well with 123I IMP-SPECT findings. This method will be useful to determine the prognosis as well as to understand changeable hemodynamic pathophysiology. A slowing of back ground on EEG also correlated well with clinical symptoms. It was necessary to examine the possibility of cerebrovascular involvement in progeria.

Amphetamines↗
PubMed1999

[Adult progeria (Werner's syndrome)].

HISTORY: A 48-year-old man was referred with progressive claudication and nocturnal pain at rest in the right foot. During the last few years exercise-induced pain, ulcerations and necroses had developed in both legs without any evidence of relevant macroangiopathies. The patient showed marked morphological changes. He had bilateral cataracts since aged 35 years. At 40 years he had undergone a transurethral resection of a bladder carcinoma. One of his brothers showed similar morphological changes, but they were absent in his parents and three siblings. INVESTIGATIONS: Radiology of the right foot revealed extensive para-osseous soft-tissue calcifications. Direct right femoral angiography demonstrated distal occlusions of the anterior and posterior tibial arteries as well as subtotal occlusion of the fibular artery. Routine laboratory tests were normal, as were all measured antibody titres. TREATMENT AND COURSE: The peripheral vascular disease, stage IV, of the right leg were presumably caused by adult progeria (Werner's syndrome). Percutaneous transluminal angioplasty (PTAP) of the distal fibular and, later, of the posterior tibial artery was performed, and prostacyclins, antibiotics and platelet-aggregation inhibitors were administered. Although the PTAP was technically successful, the state of the right foot remained critical, due to the existing microangiopathy and the impaired proliferation and healing capacity of the tissues as part of the adult progeria. CONCLUSIONS: The diagnosis of adult progeria is usually made because of the patients' characteristic morphology and typical concomitant diseases. The average age of patients at diagnosis is 37 years. The syndrome is caused by a helicase defect. This enzyme group unwinds double-helix RNA and DNA. Because the syndrome is rare and gene analysis is complex, it is unlikely that a commercial screening test will become available.

Angiography↗