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Current Opinion in Cell Biology Jun 2004The 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... (Review)
Review
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.
Topics: Animals; Cell Nucleus; Cellular Senescence; Humans; Lamins; Nuclear Envelope; Progeria; Werner Syndrome
PubMed: 15145358
DOI: 10.1016/j.ceb.2004.03.009 -
Medecine Sciences : M/S 2012
Review
Topics: Aging, Premature; Humans; Induced Pluripotent Stem Cells; MicroRNAs; Models, Biological; Neurons; Progeria
PubMed: 22805145
DOI: 10.1051/medsci/2012286022 -
Bone Aug 2019Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on...
PURPOSE
Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development.
METHODS
Children from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction.
RESULTS
Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium × phosphorus product (Ca × Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p = 0.03).
CONCLUSIONS
Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.
Topics: Calcinosis; Calcium; Child; Child, Preschool; Creatinine; Female; Fibroblast Growth Factor-23; Humans; In Vitro Techniques; Lamin Type A; Male; Parathyroid Hormone; Piperidines; Pravastatin; Progeria; Pyridines; Zoledronic Acid
PubMed: 31077852
DOI: 10.1016/j.bone.2019.05.008 -
Frontiers in Bioscience (Scholar... Jun 2011Lamin A and lamin C (A-type lamins, both encoded by the LMNA gene) are major components of the mammalian nuclear lamina, a complex proteinaceous structure that acts as a... (Review)
Review
Lamin A and lamin C (A-type lamins, both encoded by the LMNA gene) are major components of the mammalian nuclear lamina, a complex proteinaceous structure that acts as a scaffold for protein complexes that regulate nuclear structure and function. Abnormal accumulation of farnesylated-progerin, a mutant form of prelamin A, plays a key role in the pathogenesis of the Hutchinson-Gilford progeria syndrome (HGPS), a devastating disorder that causes the death of affected children at an average age of 13.5 years, predominantly from premature atherosclerosis and myocardial infarction or stroke. Remarkably, progerin is also present in normal cells and appears to progressively accumulate during aging of non-HGPS cells. Therefore, understanding how this mutant form of lamin A provokes HGPS may shed significant insight into physiological aging. In this review, we discuss recent advances into the pathogenic mechanisms underlying HGPS, the main murine models of the disease, and the therapeutic strategies developed in cellular and animal models with the aim of reducing the accumulation of farnesylated-progerin, as well as their use in clinical trials of HGPS.
Topics: Animals; Contracture; Farnesyltranstransferase; Genetic Therapy; Humans; Lamin Type A; Mice; Models, Biological; Nuclear Lamina; Nuclear Proteins; Progeria; Protein Precursors; Skin Abnormalities
PubMed: 21622261
DOI: 10.2741/216 -
Biochemical Society Transactions Dec 2011A common feature of progeria syndromes is a premature aging phenotype and an enhanced accumulation of DNA damage arising from a compromised repair system. HGPS... (Review)
Review
A common feature of progeria syndromes is a premature aging phenotype and an enhanced accumulation of DNA damage arising from a compromised repair system. HGPS (Hutchinson-Gilford progeria syndrome) is a severe form of progeria in which patients accumulate progerin, a mutant lamin A protein derived from a splicing variant of the lamin A/C gene (LMNA). Progerin causes chromatin perturbations which result in the formation of DSBs (double-strand breaks) and abnormal DDR (DNA-damage response). In the present article, we review recent findings which resolve some mechanistic details of how progerin may disrupt DDR pathways in HGPS cells. We propose that progerin accumulation results in disruption of functions of some replication and repair factors, causing the mislocalization of XPA (xeroderma pigmentosum group A) protein to the replication forks, replication fork stalling and, subsequently, DNA DSBs. The binding of XPA to the stalled forks excludes normal binding by repair proteins, leading to DSB accumulation, which activates ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) checkpoints, and arresting cell-cycle progression.
Topics: Aging; Animals; Cellular Senescence; DNA Damage; Humans; Lamins; Progeria; Signal Transduction
PubMed: 22103522
DOI: 10.1042/BST20110687 -
Journal of Medical Genetics Dec 1974A pair of male monozygotic twins, both affected by progeria is described. The concordance in this manifestation suggests a genetic aetiology and other evidence indicates...
A pair of male monozygotic twins, both affected by progeria is described. The concordance in this manifestation suggests a genetic aetiology and other evidence indicates the implication of autosomal recessive factors; the chromosomes of these patients show no detectable abnormalities.
Topics: Child; Chromosomes; Diseases in Twins; Genes, Recessive; Humans; Male; Phenotype; Progeria
PubMed: 4443987
DOI: 10.1136/jmg.11.4.384 -
Skeletal Radiology 1990The Hutchinson-Gilford progeria syndrome is a rare, inherited, pediatric condition with features of premature and accelerated aging. The pattern of inheritance is... (Review)
Review
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.
Topics: Child; Child, Preschool; Female; Humans; Male; Nigeria; Progeria; Radiography
PubMed: 2278013
DOI: 10.1007/BF00241281 -
Indian Journal of Dermatology,... 2010Progeria is a rare genetic disorder characterized by premature aging, involving the skin, bones, heart, and blood vessels. We report a 4-year-old boy who presented with...
Progeria is a rare genetic disorder characterized by premature aging, involving the skin, bones, heart, and blood vessels. We report a 4-year-old boy who presented with clinical manifestations of progeria. He had characteristic facies, prominent eyes, scalp and leg veins, senile look, loss of scalp hair, eyebrows and eyelashes, stunted growth, and sclerodermatous changes. The present case is reported due to its rarity.
Topics: Alopecia; Child, Preschool; Humans; Male; Pigmentation Disorders; Progeria; Scleroderma, Localized
PubMed: 20827016
DOI: 10.4103/0378-6323.69094 -
Nutrition Reviews Jan 1970
Review
Topics: Adrenal Glands; Amino Acids; Child; Collagen; Humans; Male; Progeria; Thyroid Gland
PubMed: 4907295
DOI: 10.1111/j.1753-4887.1970.tb06142.x -
Nepalese Journal of Ophthalmology : a... Jan 2020Progeria also known as Hutchinson Gilford Progeria Syndrome (HGPS) (MIM176670) is a very uncommon fatal genetic untimely aging syndrome. It is characterized by retarded...
INTRODUCTION
Progeria also known as Hutchinson Gilford Progeria Syndrome (HGPS) (MIM176670) is a very uncommon fatal genetic untimely aging syndrome. It is characterized by retarded physical development, accelerated degeneration of the skin, cardiovascular and musculoskeletal abnormalities. Other features include prominent eyes, thin nose, small chin and thin lips. Eyebrow hair loss, madarosis and lagopththalmos are the common ocular manifestations.
CASE
We report a case of five year old boy with complaints of discomfort in bright light and a whitish appearance in his right eye for two months. He was accompanied by the parents. They complained of loss of eyelashes and eyebrows. In the developmental history he was normal at birth till the age of one year then they noticed gradual hair fall, delayed growth, wrinkling of skin, increase in size of head and thinning of limbs.
CONCLUSION
This is the first case report from Nepal with the ocular presentation of progeria indicating the role of ocular senescence in patients with Hutchinson Progeria Gilford Syndrome.
Topics: Alopecia; Child, Preschool; Eye; Humans; Male; Nepal; Progeria; Skin
PubMed: 32799251
DOI: 10.3126/nepjoph.v12i1.25454