Approximately 90% of individuals presenting<unk>  have any of a range of mutations in the gene,<unk> , the only gene currently attributed to cause<unk> .<unk> , which lies on chromosome 8 in humans, encodes the<unk> p protein, a 1432 amino acid protein with a central domain resembling members of the RecQ helicases. RecQ helicases are a special type of helicase that function at unique times during DNA repair of doubled stranded breaks, which are a form of DNA damage that results in a break of both strands of DNA. Thus, RecQ helicases are important for maintaining DNA stability, and loss of function of these helicases has important implications in the development of<unk> . In addition to the central domain, there are three exonuclease domains at the N-terminus and a Helicase and Ribonuclease D C-terminal (HRDC) domain at the C-terminus. When functioning normally, the<unk>  gene and its associated protein <unk> p) are important for maintaining genome stability.<unk> p is active in unwinding DNA, a step necessary in DNA repair and DNA replication. Specifically, it has an important role in responding to replication malfunctions, particularly double-stranded breaks, and stalled replication machinery.<unk> p may reactivate replication by preventing unwanted recombination processes from occurring or by promoting recombination, depending on the type of DNA damage. In addition,<unk> p physically interacts with or binds to several other proteins that are involved in processing DNA. For example, when<unk> p binds to RPA, its helicase activity is stimulated.<unk> p also physically interacts with p53, a tumor suppressor gene that stops the formation of tumors and the progression of cancers, which inhibits the exonuclease activity of the<unk> p. Since<unk> p's function depends on DNA, it is only functional when localized to the nucleus. Surprisingly, complete loss of<unk>  helicase activity does not cause clinical<unk> . DNA repair processes The finding that<unk>  protein interacts with DNA-PKcs and the Ku protein complex, combined with evidence that<unk>  deficient cells produce extensive deletions at sites of joining of non-homologous DNA ends, suggests a role for<unk>  protein in the DNA repair process of non-homologous end joining (NHEJ).<unk>  protein also physically interacts with the major NHEJ factor X4L4 (XRCC4-DNA ligase 4 complex). X4L4 stimulates<unk>  exonuclease activity that likely facilitates DNA end processing prior to final ligation by X4L4.<unk>  protein appears to play a role in resolving recombination intermediate structures during homologous recombinational repair (HRR) of DNA double-strand breaks.<unk>  protein participates in a complex with RAD51, RAD54, RAD54B and ATR proteins in carrying out the recombination step during inter-strand DNA cross-link repair. Evidence was presented that<unk>  protein plays a direct role in the repair of methylation induced DNA damage. This process likely involves the helicase and exonuclease activities of<unk>  protein that operate together with DNA polymerase beta in long patch base excision repair. Effects on cell structure and function Mutations which cause<unk>  all occur at the regions of the gene which encode for protein, and not at non-coding regions. There are 35 different known mutations of<unk> , which correspond to stop codons, insertions, or deletions that result in a frameshift mutation. These mutations can have a range of effects. They may decrease the stability of the transcribed messenger RNA (mRNA), which increases the rate at which they are degraded. With less mRNA, less is available to be translated into the<unk> p protein. Mutations may also lead to the truncation (shortening) of the<unk> p protein, leading to the loss of its nuclear localization signal sequence, thus it is no longer transported into the nucleus where it interacts with the DNA. This leads to a reduction in DNA repair. Furthermore, mutated proteins are more likely to be degraded than normal<unk> p. Apart from causing defects in DNA repair, its aberrant association with p53 down-regulates the function of p53, leading to a reduction in p53-dependent apoptosis and increasing the survival of these dysfunctional cells. Cells of affected individuals also have reduced lifespan in culture, have more chromosome breaks and translocations and have extensive deletions. Patients with<unk>  lose the RecQ helicase activity in the<unk>  protein because of the loss of its C-terminus region, but the mechanism by which this happens is unclear. The loss of the helicase activity can have far-reaching consequences in terms of cell stability and mutation. One instance of these consequences involves telomeres. It is thought that the<unk>  helicase activity is important not only for DNA repair and recombination, but also for maintaining telomere length and stability. Thus,<unk>  helicase is important for preventing catastrophic telomere loss during DNA replication. In a normal cell, the telomeres (the ends of chromosomes) undergo repeated shortening during the cell cycle, which can prevent the cell from dividing and multiplying. This event can be counteracted by telomerase, an enzyme that extends the ends of the chromosomes by copying the telomeres and synthesizing an identical, but new end that can be added to the existing chromosome. However, patients with<unk>  often exhibit accelerated telomere shortening, indicating that there may be a connection between the loss of the<unk>  helicase activity and telomere and cell instability. While evidence shows that telomere dysfunction is consistent with the premature aging in<unk> , it has yet to be determined if it is the actual cause of the genomic instability observed in cells and the high rate of cancer in<unk>  patients. Without the<unk>  protein, the interwoven pathways of DNA repair and telomere maintenance fail to suppress cancer and the aging symptoms seen in patients with<unk> . Events such as rapid telomere shortening cause<unk>  cells to exhibit low responses to overall cellular stress. In addition to telomere dysfunction, over-expression of oncogenes and oxidation can induce this type of response. High stress causes a synergistic effect, where<unk>  cells become even more sensitive to agents that increase cell stress and agents that damage DNA. As a result,<unk>  cells show a drastic reduction in replicative lifespan and enter into a stage of aging prematurely. The accumulation of these damaged cells due to telomere shortening over many years may be indicative of why<unk>  symptoms only appear after an individual is about twenty years old. Protection of DNA against oxidative damage<unk>  protein was found to have a specific role in preventing or repairing DNA damages resulting from chronic oxidative stress, particularly in slowly replicating cells. This finding suggested that<unk>  may be important in dealing with oxidative DNA damage that underlies normal aging (see DNA damage theory of aging).
Werner syndrome
Mungan syndrome
Fechtner syndrome
Leschke syndrome
Klüver–Bucy syndrome
Ogden syndrome
Sugarman syndrome
Cowden syndrome