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PubMed1981

Subpopulations of human T lymphocytes. XVII. Imbalance of T cell subsets in patients with progeria and Werner's syndrome.

Peripheral blood from 4 patients with progeria and their family members and 2 patients with Werner's syndrome were analyzed for the proportion of total T cells and T cells with receptors for IgM (Tmu) or IgG (Tgamma). In 3 patients proportions of Tmu cells were within the range for age- and sex-matched controls. 1 patient had significantly lower proportions of Tmu cells when compared to age- and sex-matched controls. The proportions of Tgamma cells were increased in 2 and were within the range for normal controls in the remaining 2 patients. When data were analyzed with regard to Tmu/Tgamma ratios, 3 of 4 patients exhibited ratios lower than the lowest limit observed in age- and sex-matched controls. Surprisingly, family members in all four families exhibited patterns of Tmu and Tgamma cells similar to that seen in the patient. Both patients with Werner's syndrome had proportions of Tgamma cells, resulting in low Tmu/Tgamma ratios.

Autoantibodies↗
PubMed1990

Does progeria provide the best model of accelerated ageing in humans?

Studies of the causes of ageing are often obscured by the complexity of this phenomenon, hindering investigations in this area. In particular, the variable characteristics of ageing complicate analysis at a molecular level. It is proposed that to gain insight into ageing, the problem must first be simplified by restricting studies to an aspect of the ageing processes. It is suggested that progeria, which presents a less complicated etiology and phenotype than other accelerated ageing diseases, allows research to focus on a regulation site involved in development and ageing.

Aging↗
PubMed1994

A case of Hutchinson-Gilford progeria syndrome mimicking scleredema in early infancy.

We report a case of Hutchinson-Gilford progeria syndrome (HGPS). The patient showed the characteristics of scleredema at the age of 2.5 months but developed all the manifestations of HGPS gradually until 10 months old. The possibility of development of HGPS should by considered in any case of scleredema at birth or in early infancy.

Alopecia↗
PubMed1971

Progeria: a cell culture study on aging.

Progeria is an autosomal recessive disorder showing precocious senility. The cultured skin fibroblast from both the homozygous affected individual and the heterozygous parents can be distinguished from normals by decreased cell growth in culture. Mitotic activity, DNA synthesis, and cloning efficiency are markedly reduced.

Aging↗
PubMed2006

A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation.

Hutchinson-Gilford progeria syndrome (HGPS) is caused by the production of a truncated prelamin A, called progerin, which is farnesylated at its carboxyl terminus. Progerin is targeted to the nuclear envelope and causes misshapen nuclei. Protein farnesyltransferase inhibitors (FTI) mislocalize progerin away from the nuclear envelope and reduce the frequency of misshapen nuclei. To determine whether an FTI would ameliorate disease phenotypes in vivo, we created gene-targeted mice with an HGPS mutation (LmnaHG/+) and then examined the effect of an FTI on disease phenotypes. LmnaHG/+ mice exhibited phenotypes similar to those in human HGPS patients, including retarded growth, reduced amounts of adipose tissue, micrognathia, osteoporosis, and osteolytic lesions in bone. Osteolytic lesions in the ribs led to spontaneous bone fractures. Treatment with an FTI increased adipose tissue mass, improved body weight curves, reduced the number of rib fractures, and improved bone mineralization and bone cortical thickness. These studies suggest that FTIs could be useful for treating humans with HGPS.

Animals↗
PubMed2005

Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stress.

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare sporadic disorder with an incidence of approximately 1 per 8 million live births. The phenotypic appearance consists of short stature, sculptured nose, alopecia, prominent scalp veins, small face, loss of subcutaneous fat, faint mid-facial cyanosis, and dystrophic nails. HGPS is caused by mutations in LMNA, the gene that encodes nuclear lamins A and C. The most common mutation in subjects with HGPS is a de novo single-base pair substitution, G608G (GGC>GGT), within exon 11 of LMNA. This creates an abnormal splice donor site, leading to expression of a truncated protein. RESULTS: We studied a new case of a 5 year-old girl with HGPS and found a heterozygous point mutation, G608G, in LMNA. Complementary DNA sequencing of RNA showed that this mutation resulted in the deletion of 50 amino acids in the carboxyl-terminal tail domain of prelamin A. We characterized a primary dermal fibroblast cell line derived from the subject's skin. These cells expressed the mutant protein and exhibited a normal growth rate at early passage in primary culture but showed alterations in nuclear morphology. Expression levels and overall distributions of nuclear lamins and emerin, an integral protein of the inner nuclear membrane, were not dramatically altered. Ultrastructural analysis of the nuclear envelope using electron microscopy showed that chromatin is in close association to the nuclear lamina, even in areas with abnormal nuclear envelope morphology. The fibroblasts were hypersensitive to heat shock, and demonstrated a delayed response to heat stress. CONCLUSION: Dermal fibroblasts from a subject with HGPS expressing a mutant truncated lamin A have dysmorphic nuclei, hypersensitivity to heat shock, and delayed response to heat stress. This suggests that the mutant protein, even when expressed at low levels, causes defective cell stability, which may be responsible for phenotypic abnormalities in the disease.

Cell Nucleus↗
PubMed2005

RNAi of FACE1 protease results in growth inhibition of human cells expressing lamin A: implications for Hutchinson-Gilford progeria syndrome.

FACE 1 is the endoprotease responsible for cleavage of prelamin A to lamin A. Transfection of HeLa cells with siRNA for human FACE 1 results in a strong phenotype. Protein and mRNA levels for FACE 1 are knocked down and cell division stops abruptly. Two populations of cells are detected. The first form aberrant mitotic spindles, arrest in mitosis and later enter apoptosis. The second show dramatic changes in nuclear morphology with extensive formation of lobulated nuclei and micronuclei. Using antibodies that specifically recognise prelamin A, but not lamin A, we show that prelamin A accumulates at the nuclear lamina in FACE1 silenced cells, whereas in control cells prelamin A is found in many small nuclear dots, but not at the nuclear lamina. In double knockdown experiments with FACE 1 and lamin A siRNAs, the results depend on which protein is knocked down first. FACE1 knockdown 24 hours prior to lamin A knockdown gives results similar to the single FACE1 knockdown. By contrast, lamin A knockdown 24 hours prior to FACE1 knockdown results in none of the changes described above. Silencing of FACE1 in HL60, a cell line that lacks lamin A, also has no effect. The combined results suggest that prelamin A is a poison in cells subjected to FACE 1 knockdown. Finally, we draw attention to similarities in phenotype between FACE1-silenced HeLa cells and fibroblasts from patients with Hutchinson-Gilford progeria syndrome containing prelamin A mutations that prevent cleavage by the FACE1 endoprotease.

Cell Line↗
PubMed2006

Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles.

Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i) the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii) differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii) interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of "null" alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals.

Alleles↗
PubMed2006

Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice.

How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cultures from multiple progeroid mouse models for defects in the nucleotide excision DNA repair pathway, which share premature aging features including postnatal growth retardation, cerebellar ataxia, and death before weaning. Instead, we report a prominent phenotypic overlap with long-lived dwarfism and calorie restriction during postnatal development (2 wk of age), including reduced size, reduced body temperature, hypoglycemia, and perturbation of the growth hormone/insulin-like growth factor 1 neuroendocrine axis. These symptoms were also present at 2 wk of age in a novel progeroid nucleotide excision repair-deficient mouse model (XPD(G602D/R722W)/XPA(-/-)) that survived weaning with high penetrance. However, despite persistent cachectic dwarfism, blood glucose and serum insulin-like growth factor 1 levels returned to normal by 10 wk, with hypoglycemia reappearing near premature death at 5 mo of age. These data strongly suggest changes in energy metabolism as part of an adaptive response during the stressful period of postnatal growth. Interestingly, a similar perturbation of the postnatal growth axis was not detected in another progeroid mouse model, the double-strand DNA break repair deficient Ku80(-/-) mouse. Specific (but not all) types of genome instability may thus engage a conserved response to stress that evolved to cope with environmental pressures such as food shortage.

Aging↗
PubMed2025

Pharmacologic activation of Δ133p53α reduces cellular senescence in progeria patients-derived cells.

BACKGROUND: Patients with Hutchinson-Gilford progeria syndrome (HGPS) show accelerated aging phenotypes and have shortened lifespan, with implications in physiological aging processes as well. While therapeutic approaches targeting the disease-causing abnormal protein, progerin, have been developed, further efforts to explore mechanistically distinct and complementary strategies are still critical to better treatment regimens. We previously showed that lentiviral vector-driven expression of Δ133p53α, a natural inhibitory isoform of p53, rescued HGPS patients-derived fibroblasts from early entry into cellular senescence, which is a downstream event of progerin-induced DNA damage. We also performed a quantitative high-throughput screen (qHTS) of approved drug and investigational agent libraries, leading to the identification of celastrol and AZD1981 as compounds that upregulate Δ133p53α protein levels. METHODS: To investigate whether celastrol and ADZ1981 upregulate endogenous Δ133p53α in HGPS-derived fibroblasts and reduce their senescence-associated phenotypes, we performed western blot assays (Δ133p53α, progerin, and p21WAF1, which mediates p53-induced senescence and is inhibited by Δ133p53α), senescence-associated β-galactosidase (SA-β-gal) staining, enzyme-linked immunosorbent assay (IL-6, which is a proinflammatory cytokine secreted from senescent cells), and qRT-PCR assays (p21WAF1 and IL-6). RESULTS: Treatment with celastrol (0.1 μM for 24 h) or AZD1981 (10 μM for 24 h) reproducibly increased Δ133p53α expression and decreased p21WAF1 expression in two strains of fibroblasts derived from HGPS patients. These compounds reduced the percentage of SA-β-gal-positive senescent cells and the secretion of IL-6 into culture medium in both of these fibroblast strains, irrespective of their different basal levels of senescence and IL-6 secretion. These compounds had no effect on the level of progerin. CONCLUSION: Celastrol and ADZ1981 upregulate endogenous Δ133p53α and, reproducing the effects of its vector-driven expression, inhibit cellular senescence and IL-6 secretion in HGPS-derived fibroblasts. Their progerin-independent action suggests that they may synergize with currently available progerin-targeting therapies. This study also warrants further investigation of these compounds for potential applications in other diseases and conditions in which Δ133p53α-regulated senescence plays a role.

Hutchinson-Gilford progeria syndrome↗
PubMed1999

[Gilford progeria. A case report].

Hutchinson-Gilford progeria syndrome is a rare syndrome of premature aging with multiple skeletal abnormalities. We report one case. The literature is reviewed. Characteristics of 30 patients with radiological records are presented. Pronounced acro-osteolysis, osteolysis of the clavicle are the main features. Modern imaging is useful to diagnose the complications.

Adolescent↗
PubMed1976

Progeria, a case report from Iran.

A 4 1/4-year-old male child with the Hutchinson-Gilford progeria syndrome is described. This is the first case to be reported from Iran.

Child, Preschool↗
PubMed1991

Progeria syndrome with characteristic deformation of proximal radius observed on CT.

The progeria syndrome (Hutchinson-Gilford) is an uncommon disease. A peculiar shape of the proximal radial metaphyseal region caused by an infolding of the cortex was observed on CT in 2 brothers suffering from this disorder, a feature not previously reported. A brief review of the radiologic literature was undertaken. This new observation needs to be further evaluated as it may provide a clinching diagnostic feature of this disease.

Adult↗
PubMed1989

Progeria.

Progeria, also known as the Hutchinson-Gilford syndrome, is an extremely rare condition that was initially reported by Johnathan Hutchinson in 1886 and further described by Hastings Gilford in 1904. Transmission is most likely from a sporadic autosomal dominant mutation. Clinical manifestations are evident by the first or second year of life and include the physical characteristics usually associated with the elderly. Mentally, patients are alert and attentive with normal intelligence and emotions. Histopathologic changes occur primarily in the skin, bone, and cardiovascular tissues, while other organs appear to be unaffected. Laboratory findings are unremarkable, with the exception of an increased urinary excretion of hyaluronic acid. The diagnosis rests on the clinical presentation; at present, no treatment has been proved to be effective. Death results from cardiovascular abnormalities in the majority of cases and usually occurs between the ages of 10 and 15 years. Current research suggests an underlying defect of hyaluronic acid that may possibly account for the entire process.

Aging↗
PubMedDate not supplied

[Hutchinson-Gilford progeria. A rare case of neonatal occurrence].

A case of Hutchinson-Gilford progeria syndrome is described in which phenotypic and metabolic symptoms were already evident at birth. Both under a clinical and autopsy point of view an early old age of organs and apparatuses was apparent, posing the problem of the reason why an early old aging occurs. The authors mention literature in favour of a genetic control of cellular aging and make the assumption that the genes controlling old age are various and that a greater or lesser presence and incidence of them could justify the earlier or normal appearance of this status.

Humans↗
PubMed1984

Hip disease in Hutchinson-Gilford progeria syndrome.

Two cases of Hutchinson-Gilford progeria syndrome are presented with a focus on hip disease. A severe coxa valga is the first abnormality. The femoral head becomes increasingly uncovered as the acetabulum becomes more dysplastic. The center edge angle decreases, the acetabular index increases, and the medial wall of the acetabulum widens. Hip pain, subluxation, and eventually dislocation are the sequelae of these changes. Late osteotomy is unpredictable; thus the best therapeutic regimen is early osteotomy (age 4-6 years) and a regular exercise program to maintain muscle strength and range of motion.

Acetabulum↗
PubMed1981

Cardiovascular abnormalities in progeria. Case report and review of the literature.

The cardiovascular findings in cases of progeria are similar in many respects to the changes associated with aging. These changes include prominent atherosclerosis and calcification of the aortic and mitral valves, coronary arteries, and aorta. The coronary artery disease leads to ischemic changes in the myocardium, including well-defined infarcts. In addition, the present case demonstrates narrowing of the small intramural arteries, which may have contributed to myocardial fibrosis.

Adolescent↗
PubMed1982

[Werner syndrome-like disease in 3 brothers. Differential diagnosis of progeria syndrome].

A report is given on a progeroid disease affecting three brothers, 11, 13, and 14 years old. The difficult differential diagnosis of such progeroid syndromes is discussed. The clinical signs were mostly consistent with Werner's syndrome. Since some of the symptoms of this disease were not present, probably because of the young age of the patients, this progeroid syndrome was classified as Werner syndrome-like. Electronmicroscopic findings of the patients skin showed changes of the blood vessels and nerves, which were until now not described in Werner's syndrome or other progerias. The latter findings may give some hints with regard to the pathogenesis of this disease.

Adolescent↗