Progeria syndromes

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Progeria syndromes

Progeria is a rare genetic disease with striking features that resemble accelerated aging. The inheritance pattern, paternal age effect, and lack of consanguinity argue that it is due to a sporadic dominant mutation. 

The nuclear lamina is a network of structural filaments, the A and B type lamins, located at the nuclear envelope and throughout the nucleus. Lamin filaments provide the nucleus with mechanical stability and support many basic activities, including gene regulation. Mutations in LMNA, the gene encoding A type lamins, cause numerous human diseases, including the segmental premature aging disease Hutchinson–Gilford progeria syndrome (HGPS). Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disease that causes segmental premature aging in children. HGPS patients are mentally normal, but fail to reach full stature and experience hair loss, thin wrinkled skin, and joint stiffness, and usually die in their early teens of cardiovascular disease or stroke.

Bloom syndrome (BS) is an autosomal recessive disorder characterized by a high incidence of cancer and genomic instability. BLM, the protein defective in BS, is a RecQ-like helicase, presumed to function in DNA replication, recombination, or repair. BLM localizes to promyelocytic leukemia protein (PML) nuclear bodies and is expressed during late S and G2. LM colocalizes with a select subset of telomeres in normal cells and with large telomeric clusters seen in simian virus 40-transformed normal fibroblasts.

Werner syndrome (WS) is an uncommon autosomal recessive disorder characterized by premature aging. The clinical manifestations of WS, including atherosclerosis and osteoporosis, appear early in adulthood, and death in the fourth to sixth decade commonly ensues from myocardial infarction or cancer. In accord with the aging phenotype, cells from WS patients have a reduced replicative life span in culture. Genomic instability is observed at the cytogenetic level in the form of chromosome breaks and translocations and at the molecular level by multiple large deletions. The gene defective in WS encodes a 3' --> 5' DNA helicase.

Rothmund-Thomson syndrome (RTS) is a genodermatosis presenting with a characteristic facial rash (poikiloderma) associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging and a predisposition to cancer. The prevalence is unknown but around 300 cases have been reported in the literature so far. The diagnostic hallmark is facial erythema, which spreads to the extremities but spares the trunk, and which manifests itself within the first year and then develops into poikiloderma. Two clinical subforms of RTS have been defined: RTSI characterized by poikiloderma, ectodermal dysplasia and juvenile cataracts, and RTSII characterized by poikiloderma, congenital bone defects and an increased risk of osteosarcoma in childhood and skin cancer later in life. RTS-II is caused by homozygous or compound heterozygous (frameshift/missense) mutations in RECQL4 DNA helicase gene.