SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
We have studied a boy with progeria (Hutchinson Gilford) born to third cousins. Four other individuals with progeria were born in another consanguineous sibship in the same family. Thus, this disorder can be inherited as an autosomal recessive trait.
We report a young girl with a phenotype combining early-onset myopathy and a progeria. She had myopathy and marked axial weakness during the first year of life; progeroid features, including growth failure, sclerodermatous skin changes, and osteolytic lesions, developed later. We identified the underlying cause to be a hitherto unreported de novo missense mutation in the LMNA gene (S143F) encoding the nuclear envelope proteins lamins A and C. Although LMNA mutations have been known to cause Hutchinson-Gilford progeria syndrome and Emery-Dreifuss muscular dystrophy, this is the first report of a patient combining features of these two phenotypes because of a single mutation in LMNA.
In vitro cellular senescence of human diploid fibroblast has been a good model for aging research, which shows similar phenotypes to in vivo aging. Gene expression profiling would provide an insight to understand the mechanism of senescence. Using cDNA microarray containing 384 known genes, we compared the expression profiles of three different types of aging models: replicative senescence, fibroblasts from progeria or from elderly donor. Although all of them showed senescence phenotypes, distinct sets of genes were altered in each group. Pairwise plots or cluster analysis of activation fold of gene expression revealed closer relationships between fibroblasts from progeria or from old individual, but not between replicative senescence fibroblasts and either models. Differential expression pattern of several genes were confirmed by RT-PCR. We suggest that the replicative senescence model might behave differently to other types of aging models due to the distinct gene expression.
This report relates the case histories of two sisters who demonstrated the typical symptoms of progeria at birth. One of these children had died previous to this study. The familial occurrence underlines the thesis that progeria is an autosomal-recessive disorder. The examination of the cultured skin fibroblasts from the younger child showed a clear decrease in cell growth. On the other hand, the immunfluorescent examination of skin biopsies and cultured skin fibroblasts revealed no atypical distribution of collagen types.
Hutchinson-Gilford progeria (HGPS) is a premature aging syndrome associated with LMNA mutations. Progeria cells bearing the G608G LMNA mutation are characterized by accumulation of a mutated lamin A precursor (progerin), nuclear dysmorphism and chromatin disorganization. In cultured HGPS fibroblasts, we found worsening of the cellular phenotype with patient age, mainly consisting of increased nuclear-shape abnormalities, progerin accumulation and heterochromatin loss. Moreover, transcript distribution was altered in HGPS nuclei, as determined by different techniques. In the attempt to improve the cellular phenotype, we applied treatment with drugs either affecting protein farnesylation or chromatin arrangement. Our results show that the combined treatment with mevinolin and the histone deacetylase inhibitor trichostatin A dramatically lowers progerin levels, leading to rescue of heterochromatin organization and reorganization of transcripts in HGPS fibroblasts. These results suggest that morpho-functional defects of HGPS nuclei are directly related to progerin accumulation and can be rectified by drug treatment.
Human fibroblast cells from two different progeroid syndromes, Werner syndrome (WS) and progeria, were established as immortalized cell lines by transfection with plasmid DNA containing the SV40 early region. The lineage of each immortalized cell line was confirmed by VNTR analysis. Each of the immortalized cell lines maintained its original phenotype of slow growth. DNA repair ability of these cells was also studied by measuring sensitivity to killing by uv or the DNA-damaging drugs methyl methansulfonate, bleomycin, and cis-dichlorodiamine platinum. The results showed that both WS and progeria cells have normal sensitivity to these agents.
Triosephosphate isomerase was found to have an increased thermolabile component in skin fibroblasts from patients with progeria and Werner's syndrome when compared with normal fibroblasts. Mixtures of cell extracts from progeria or Werner's syndrome with normal fibroblasts gave intermediate levels of the heat-labile triosephosphate isomerase suggesting the absence of cytosolic destabilizing factors. The incorporation of the protease inhibitors 1-tosylamide-2-phenylethyl chloromethyl ketone, N-alpha-p-tosyl-L-lysine chloromethyl ketone, phenylmethyl-sulfonyl fluoride, and pepstatin A in cell extracts failed to affect the level of the labile form of triosephosphate isomerase. The labile component also accumulates in normal fibroblasts in late passage in tissue culture and appears to be identical to the deamidated form of the enzyme which accumulates in other aging cells.
Hutchinson-Gilford progeria was observed in two brothers. Their parents, sister and other relatives did not show any signs of this illness. Serum total cholesterol and total triglyceride levels were normal in the whole family. The serum high density lipoprotein cholesterol (HDL-C) level of parents was low and that of boys was extremely low. The serum HDL-C level of the healthy sister and other relatives was normal. These findings in homozygous children and heterozygous parents may explain the development of the very early fatal arteriosclerosis described in this disease. The connection between the disorder of the lipid metabolism and progeria can serve as a useful model in the study of the role of lipid metabolism in normal ageing.
Interest in the pharmacological effects of drugs in the elderly has created a need for a laboratory model in which responses of aged animals to drugs can be studied. Dihydrotachysterol (DHT)-induced progeria, a syndrome with symptoms similar to those seen in normal aging, was evaluated as an old age model. DHT-treatment was shown to produce a decreased carbohydrate tolerance that was due to an impaired release of insulin from pancreatic islets and not due to a decreased sensitivity to insulin. These changes were unlike those observed with aging. Thus, DHT-induced progeria would not appear to be a good model for aging for the investigation of carbohydrate metabolism. Evidence is presented which indicates that glucose and tolbutamide act via different mechanism to stimulate insulin release.
A patient with unusual Hutchinson-Gilford syndrome (progeria) is reported. This 7-year-old boy had all the characteristics of progeria, except for coxa valga and the "horse-riding" stance. A previous cerebral infarction was detected in the right putamen on cranial magnetic resonance imaging. During treadmill exercise test electrocardiography, ST depression suggested the existence of arteriosclerotic lesions. Skin fibroblast culture exhibited 76% DNA-repair capacity compared to normal. He has not manifested endocrinologic abnormalities. From these findings it is concluded that this patient has an incomplete case of Hutchinson-Gilford syndrome and that a correlation may exist between the clinical features and the degree of DNA-repair capacity.
Inborn defects in nucleotide excision DNA repair (NER) can paradoxically result in elevated cancer incidence (xeroderma pigmentosum [XP]) or segmental progeria without cancer predisposition (Cockayne syndrome [CS] and trichothiodystrophy [TTD]). We report generation of a knockin mouse model for the combined disorder XPCS with a G602D-encoding mutation in the Xpd helicase gene. XPCS mice are the most skin cancer-prone NER model to date, and we postulate an unusual NER dysfunction that is likely responsible for this susceptibility. XPCS mice also displayed symptoms of segmental progeria, including cachexia and progressive loss of germinal epithelium. Like CS fibroblasts, XPCS and TTD fibroblasts from human and mouse showed evidence of defective repair of oxidative DNA lesions that may underlie these segmental progeroid symptoms.
The discoveries of at least eight human diseases arising from mutations in LMNA, which encodes the nuclear A-type lamins, have revealed the nuclear envelope as an organelle associated with a variety of fundamental cellular processes. The most recently discovered diseases associated with LMNA mutations are the premature aging disorders Hutchinson-Gilford progeria syndrome (HGPS) and atypical Werner's syndrome. The phenotypes of both HGPS patients and a mouse model of progeria suggest diverse compromised tissue functions leading to defects reminiscent of aging. Aspects of the diseases associated with disrupted nuclear envelope/lamin functions may be explained by decreased cellular proliferation, loss of tissue repair capability and a decline in the ability to maintain a differentiated state.
The relationship between progerias--diseases that resemble premature aging--and the normal aging process has been a source of debate in the aging research community. A recent study finds that LMNA, a gene targeted for mutation in Hutchinson Gilford Progeria Syndrome, may control the onset of aging-associated decline in normal fibroblasts.
Hutchinson-Gilford progeria syndrome is a rare genetic disorder that mimics certain aspects of aging prematurely. Recent work has revealed that mutations in the lamin A gene are a cause of the disease. We show here that cellular aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by a period of hyperproliferation and terminates with a large increase in the rate of apoptosis. The occurrence of cells with abnormal nuclear morphology reported by others is shown to be a result of cell division since the fraction of these abnormalities increases with cellular age. Similarly, the proportion of cells with an abnormal or absent A-type lamina increases with age. These data provide clues as to the cellular basis for premature aging in HGPS and support the view that cellular senescence and tissue homeostasis are important factors in the normal aging process.
Proline/arginine-rich end leucine-rich repeat protein (PRELP) a small leucine-rich proteoglycan (SLRP), binds type I collagen to basement membranes and type II collagen to cartilage. Evidence for lack of binding of collagen in basement membranes and cartilage of Hutchinson-Gilford progeria (HGP) cases suggests PRELP involvement in that disease. PRELP deficiency is able to account for many symptoms of HGP. Moreover, PRELP also accounts for the fact that unlike many other collagen-related diseases, HGP symptoms are not congenital. The appearance of PRELP sometime after the third month of the birth, coincides with the appearance of HGP symptoms. Hutchinson-Gilford progeria has been diagnosed in twins with a chromosomal inversion at, or very near, the site of the PRELP gene.
The Hutchinson-Gilford syndrome, commonly referred to as progeria, is a rare childhood syndrome that results in premature ageing. We focus on two anaesthetics administered to a child with progeria and a review of the available literature.
Hutchinson-Gildford syndrome is an extremely rare condition characterized by the appearance of accelerated ageing. Reports of general anaesthesia in a child with progeria within the last 20 years in the English-spoken literature are very rare. We report a case of general anaesthesia in a 12-year-old boy with this condition. The child had a past history of failed intubation. Key points in the management of anaesthesia in progeria are discussed.
Progeria infantum (Hutchinson-Gilford syndrome) is a very rare syndrome of premature aging characterized by growth retardation and specific, progressive, premature senescent changes of the skin and other tissues. We report a 1.5-year-old girl with loss of scalp hair, eyebrows, and lashes, prominent scalp veins, micrognathia, abnormal ears, loss of subcutaneous tissue, and scleroderma-like areas over the trunk. Radiographic studies revealed coxa valga and acro-osteolysis of the terminal phalanges. The clinical and radiologic features corresponded well with progeria infantum.