Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied a 15-year-old girl (P1) suffering from the Hutchinson-Gilford syndrome (progeria) associated with a severe insulin resistance. Insulin binding activity to P1 erythrocytes was 85% reduced when compared to that measured in ten normal controls matched for sex and age. This finding was confirmed in Epstein-Barr virus (EBV)-transformed lymphoblasts and depends on a reduction in insulin receptor number. Also the amount of total insulin receptors, [35S]methionine labeled and immunoprecipitated, was 90% reduced in P1 lymphoblasts when compared to controls. Next, we measured insulin receptor mRNA levels and we found undetectable levels of insulin receptor transcript in P1 EBV-transformed lymphoblasts, in the absence of any rearrangement of insulin receptor gene as evaluated by Southern blot analysis. The marked reduction in insulin receptor gene expression probably accounts for the severe insulin resistance presented by the patient. Despite extensive studies, the molecular basis of progeria is still unknown. The near complete absence of a molecule crucial in the transduction of cell growth and differentiation signals could be involved in the accelerated aging of the patient.
Mol Cell Endocrinol 1991 Jan
PMID:Insulin receptor gene expression is reduced in cells from a progeric patient. 164 40

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.
Mol Cell Biochem 1993 Mar 10
PMID:Elevated levels of glycoprotein gp200 in progeria fibroblasts. 845 3

A number of mouse models have been identified and are being used for aging and age-associated disease research. However, the use of the genetically manipulated mouse model is still a relatively untapped resource for the study of the biology of aging. Genetically altered mice can be powerful tools for biology of aging research because gene expression can be controlled and correlated with established biomarkers. Standard transgene overexpression and gene targeting techniques were modified and used to generate 30 mouse lines during a 4-year period. These lines include models of Werner's syndrome (premature aging or progeria), Alzheimer's disease, other neurodegenerative condition, atherosclerosis, diabetes, immune dysfunction, musculoskeletal disorders, and oxidative stress. These new mouse models are providing additional insights into aging processes and will be useful for developing intervention strategies and collaborative interactions.
Exp Mol Pathol 2002 Feb
PMID:Generation of genetically altered mouse models for aging studies. 1178 22

Hutchinson-Gilford progeria syndrome is an extremely rare condition with features of premature and accelerated aging. The pattern of inheritance if unclear, although both autosomal recessive and autosomal dominant modes have been proposed. The children usually present in late infancy and early childhood with a characteristic phenotype of alopecia; short stature; abnormal skin, teeth, and nails; beaked nose; loss of subcutaneous fat; and failure to thrive. This condition has been reported on all inhabited continents and has been described in all major races. Laboratory findings note an increased urinary excretion of hyaluronic acid. Death results from cardiovascular abnormalities in the majority of cases and usually occurs in the second decade of life. There is no effective treatment. We report the pathologic changes noted at autopsy on a 20-year-old woman with classic features of Hutchinson-Gilford progeria syndrome.
Pediatr Pathol Mol Med
PMID:Hutchinson-Gilford progeria syndrome: a pathologic study. 1184 74

Mutations affecting the coding sequence of intermediate filament (IF) proteins account for >30 disorders, including numerous skin bullous diseases, myopathies, neuropathies, and even progeria. The manipulation of IF genes in mice has been widely successful for modeling key features of such clinically distinct disorders. A notable exception is pachyonychia congenita (PC), a disorder in which the nail and other epithelial appendages are profoundly aberrant. Most cases of PC are due to mutations in one of the following keratin-encoding genes: K6, K16, and K17. Yet null alleles obliterating the function of both K6 genes (K6alpha and K6beta) or the K17 gene, as well as the targeted expression of a dominant-negative K6alpha mutant, elicit only a subset of PC-specific epithelial lesions (excluding that of the nail in mice). We show that newborn mice null for K6alpha, K6beta, and K17 exhibit severe lysis restricted to the nail bed epithelium, where all three genes are robustly expressed, providing strong evidence that this region of the nail unit is initially targeted in PC. Our findings point to significant redundancy among the multiple keratins expressed in hair and nail, which can be related to the common ancestry, clustered organization, and sequence relatedness of specific keratin genes.
Mol Cell Biol 2005 Jan
PMID:Overcoming functional redundancy to elicit pachyonychia congenita-like nail lesions in transgenic mice. 1560 42

Many nuclear proteins form lamin-dependent complexes, including LEM-domain proteins, nesprins and SUN-domain proteins. These complexes have roles in chromatin organization, gene regulation and signal transduction. Some link the nucleoskeleton to cytoskeletal structures, ensuring that the nucleus and centrosome assume appropriate intracellular positions. These complexes provide new insights into cell architecture, as well as a foundation for the understanding of the molecular mechanisms that underlie the human laminopathies - clinical disorders that range from Emery-Dreifuss muscular dystrophy to the accelerated ageing seen in Hutchinson-Gilford progeria syndrome.
Nat Rev Mol Cell Biol 2005 Jan
PMID:The nuclear lamina comes of age. 1568 64

Restrictive dermopathy (RD) is characterized by intrauterine growth retardation, tight and rigid skin with prominent superficial vessels, bone mineralization defects, dysplastic clavicles, arthrogryposis and early neonatal death. In two patients affected with RD, we recently reported two different heterozygous splicing mutations in the LMNA gene, leading to the production and accumulation of truncated Prelamin A. In other patients, a single nucleotide insertion was identified in ZMPSTE24. This variation is located in a homopolymeric repeat of thymines and introduces a premature termination codon. ZMPSTE24 encodes an endoprotease essential for the post-translational cleavage of the Lamin A precursor and the production of mature Lamin A. However, the autosomal recessive inheritance of RD suggested that a further molecular defect was present either in the second ZMPSTE24 allele or in another gene involved in Lamin A processing. Here, we report new findings in RD linked to ZMPSTE24 mutations. Ten RD patients were analyzed including seven from a previous series and three novel patients. All were found to be either homozygous or compound heterozygous for ZMPSTE24 mutations. We report three novel 'null' mutations as well as the recurrent thymine insertion. In all cases, we find a complete absence of both ZMPSTE24 and mature Lamin A associated with Prelamin A accumulation. Thus, RD is either a primary or a secondary laminopathy, caused by dominant de novo LMNA mutations or, more frequently, recessive null ZMPSTE24 mutations, most of which lie in a mutation hotspot within exon 9. The accumulation of truncated or normal length Prelamin A is, therefore, a shared pathophysiological feature in recessive and dominant RD. These findings have an important impact on our knowledge of the pathophysiology in Progeria and related disorders and will help direct the development of therapeutic approaches.
Hum Mol Genet 2005 Jun 01
PMID:Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors. 1584 3

Hutchinson-Gilford progeria syndrome (HGPS) is typically caused by mutations in codon 608 (G608G) of the LMNA gene, which activates a cryptic splice site resulting in the in-frame loss of 150 nucleotides from the lamin A message. The deleted region includes a protein cleavage site that normally removes 15 amino acids, including a CAAX box farnesylation site, from the lamin A protein. We investigated the processing of the C-terminus of the mutant protein, 'progerin', and found that it does not undergo cleavage and, indeed, remains farnesylated. The retention of the farnesyl group may have numerous consequences, as farnesyl groups increase lipophilicity and are involved in membrane association and in protein interactions, and is likely to be an important factor in the HGPS phenotype. To further investigate this, we studied the effects of farnesylation inhibition on nuclear phenotypes in cells expressing normal and mutant lamin A. Expression of a GFP-progerin fusion protein in normal fibroblasts caused a high incidence of nuclear abnormalities, as was also seen in HGPS fibroblasts, and resulted in abnormal nuclear localization of GFP-progerin in comparison with the localization pattern of GFP-lamin A. Expression of a GFP-lamin A fusion containing a mutation preventing the final cleavage step, causing the protein to remain farnesylated, displayed identical localization patterns and nuclear abnormalities as in HGPS cells and in cells expressing GFP-progerin. Exposure to a farnesyltransferase inhibitor (FTI), PD169541, caused a significant improvement in the nuclear morphology of cells expressing GFP-progerin and in HGPS cells. These results implicate the abnormal farnesylation of progerin in the cellular phenotype in HGPS cells and suggest that FTIs may represent a therapeutic option for patients with HGPS.
Hum Mol Genet 2005 Oct 15
PMID:Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. 1612 33

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.
Cell Mol Life Sci 2005 Nov
PMID:Rescue of heterochromatin organization in Hutchinson-Gilford progeria by drug treatment. 1626 Dec 60

Over the last years it has become evident that the nuclear envelope (NE) is more than a passive membrane barrier that separates the nucleus from the cytoplasm. The NE not only controls the trafficking of macromolecules between the nucleoplasm and the cytosol, but also provides anchoring sites for chromosomes and cytoskeleton to the nuclear periphery. Targeting of chromatin to the NE might actually be part of gene expression regulation in eukaryotes. Mutations in certain NE proteins are associated with a diversity of human diseases, including muscular dystrophy, neuropathy, lipodistrophy, torsion dystonia and the premature aging condition progeria. Despite the importance of the NE for cell division and differentiation, relatively little is known about its biogenesis and its role in human diseases. It is our goal to provide a comprehensive view of the NE and to discuss possible implications of NE-associated changes for gene expression, chromatin organization and signal transduction.
Cell Mol Life Sci 2006 Feb
PMID:The role of the nuclear envelope in cellular organization. 1638 59


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