User:Kinkreet/Progeroid Syndrome 0

Progeroid syndromes (PSs)
Progeroid syndromes (PSs) is the name of a group of disorders that mimic aging at an early age. Some disorders shows hallmarks of aging, whereas others do not; it can affect one organ or many. Segmental progeroid syndromes are PSs which do not associate with all aspects of physiological aging; examples include Werner syndrome, Hutchinson-Gilford progeria, ataxia telangiectasia, dyskeratosis congenita and Bloom syndrome. Other PSs affects only one organ, and includes familial Alzheimer's disease, familial Parkinson's disease.

PS can be separated into sub-groups corresponding to the cause of the disorder, which includes mutations in the genes encoding for DNA repair, usually DNA helicase, and genes affecting the structure or post-translational maturation of lamin A, a nuclear intermediate filament constituting large parts of the nuclear lamina.

Different segmental progerias have suggested that maintaining a stable genome and nuclear environment is essential for keeping away from senescence. However, questions arise as to whether these Progeroid syndromes really represents normal aging.

Werner Syndrome
Werner syndrome is a very rare autosomal recessive disorder. WS clinical signs include altered distribution of subcutaneous fat, juvenile bilateral cataracts, a mask-like face and bird-like nose, trophic ulcers of the feet, diabetes mellitus, and premature atherosclerosis. The habitus is characteristic, with short stature, stocky trunk and slender extremities. WS frequency has been roughly estimated to be 1: 100,000 in Japan and 1: 1,000,000-1: 10,000,000 outside of Japan.

WS is caused by mutations in the WRN gene, which is located on the short arm of chromosome 8 (locus 8p12-p11.2) and encodes for a RecQ DNA helicase with 3' to 5' exonuclease activity (used to unwind and repair DNA, recombination and maintenance of telomeres). The mutation occurs between residues 949-1092, and causes the helicase to lose its nuclear localization signal (NLS) , which means it cannot bind to DNA to repair it. This results in mis-recombination and telomere shortening; ultimately, the cells will try to safeguard themselves by entering prematurely into senescence. Patients do not show signs of aging until puberty and late adolescence, when they'd stop growing and show premature aging. Symptoms includes cataracts, grey hair, osteoporosis, cancer, artherosclerosis, poor glucose regulation, skin atrophy and myocardial infarction. The median lifespan of a WS patient is 47-48 years old, and they usually die from myocardiac infarction and/or cancer. Fertility is greatly reduced for individuals with Werner syndrome, possibly due to accelerated loss of priomordial follicles in the ovaries, and testicular atrophy. There is currently no cure for this disease.

A mouse model with the Werner protein knocked out do not show degerenative properties.

Hutchinson-Gilford Progeria Syndrome (HGPS)
Hutchinson-Gilford Progeria is similar to Werner syndrome, only that it manifests usually before 12 months to 2 years of age. Patients have very thin skin, lose subcutaneous fat, alopecia (loss of body hair), stiff joints and osteoporosis. The median lifespan is 13 years, and patients usually die by stroke or heart attack, although cancer is not very prevalent.

HGPS is caused by a dominant mutation in lamin A which causes 50 amino acids to be incorrectly spliced out, and causes the progerin protein to remain farnesylated. Lamin A is the major constituent of the nuclear lamina, and its mutation leads to a distorted nucleus. A dysfunctional nuclear lamina may lead to a lack of β-catenin entering the nucleus, because it can no longer interact with the nuclear pore. This leads to reduced Lef1 activity, which reduces Wnt signalling. The lack of Wnt signalling leads to reduced ECM production. Fibroblasts require ECM to grow on, and thus the lack of ECM leads to a halt in the proliferation of fibroblast and this may be fatal. This also explains by HGPS patients have very thin skin and blood vessels, and also skeletal problems.

HGPS cells in culture have reduced lifespan, its nucleus looks distorted, have less heterochromatin and many binuclear cells exist. The chromosomes have shortened telomeres, as well as aggregation of telomeres. Chronic DNA-damage response where progerin signals to p53 and Rb to cause early cell senescence. Gene transcription are modified and DNA repair is reduced in HGPS cells.

Ataxia telangiectasia (A-T)
Ataxia telangiectasia (A-T) is another rare autosomal segmental progeroid synrome. A-T is caused by mitations in the ATM gene, a kinase that phosphorylates proteins involved in DNA damage signalling, DNA repair and telomere maintenance. A-T cells exhibits premature senescence, genome instability and telomere shortening. Symptoms includes progressive cerebellar degeneration (ataxia), skin abnormalities and immunodeficiency.

A mouse model with the ATM knocked out do not show degerenative properties.

Dyskeratosis congenita (DC)
Dyskeratosis congenita (DC) is a rare hereditary disorder usually present in males. It is caused by mutations in 6 DC genes which are normally involved in telomere maintenance; its mutation leads to genomic instability. Symptoms of DC includes cancer, grey hair and osteoporosis at an early age, and affects the mucous membranes, teeth, nails, skin pigmentation. The disease state of DC can be studied using iPSCs, to give an in vitro human model of the disease. When DC fibroblasts are transfected with OCT4, SOX2, KLF4 and c-MYC, the resulting iPSCs have longer telomeres, due to the induction of telomerase reverse transcriptase gene (TERT). The RNA component (TERC) were upregulated in these reprogrammed iPSCs. When these iPSCs differentiate, trasncription of TERT is silenced and the RNA component is deleted at the 3' end; the telomeres get shorter once more.

Cockayne syndrome (CS)
Cockayne syndrome (CS) is a rare segmental progeroid syndrome. CS is caused by a mutation in the Cockayne syndrome complementation group B (CSB) gene, which lies within the CSA gene. CSB encodes for a DNA-dependent ATPase, which dimer is wrapped around by DNA; CSA encodes for a component of a ubiquitin ligase complex. Their mutation means they cannot repair oxidation-induced damage to the DNA, and thus any mutations during replication is likely to remain. It also stalls the RNA Pol II as the TCR which normally removes the stall RNA Pol II can no longer perform its function, as a co-factor (CSB) is missing. Mutations in the CSA gene can be as detrimental, as CSB needs to be ubiquinated (by CSA) for repair to occur. This means CS patients are sensitve to DNA damage especially UV, and thus must remain in doors away from UV as much as possible. CS leads to progressive neurological degeneration, hearing loss and cataracts. The mean life span is 12 years.