Cells from people with Bloom syndrome have been found to have abnormal responses to UV radiation. Normal nuclear accumulation of TP53 after UV radiation was absent in 2 of 11 primary cultures from individuals with Bloom syndrome; in contrast, responses in cultures from people who have XP and ataxia-telangiectasia were normal. The gene product of the BLM gene has also been found to complex with Fanconi proteins, raising the possibility of connections between the BLM and Fanconi anemia pathways for DNA stability.
Like Bloom syndrome, Werner syndrome is characterized by spontaneous chromosomal instability, resulting in increased susceptibility to cancer and premature aging. Diagnostic criteria, often in the setting of consanguinity, include cataracts, short stature, premature graying or thinning of hair, and a positive 24-hour urinary hyaluronic acid test. Cardinal cutaneous manifestations of this disorder consist of sclerodermatous skin changes, ulcerations, atrophy, and pigmentation changes. Individuals with this syndrome have an average life expectancy of fewer than 50 years. Cancers have an early onset and occur in up to 43% of these patients. The spectrum of tumors associated with this disorder has primarily been described in the Japanese population and includes an increased incidence of sarcoma, thyroid cancers and skin cancers. Approximately 20% of the cancers reported in this syndrome are cutaneous, with melanoma and SCC of the skin accounting for 14% and 5%, respectively. Acral lentiginous melanomas are overrepresented, and SCCs may exhibit more aggressive behavior, with metastasis to lymph nodes and internal organs.[167,169]
Mutations in the WRN gene on chromosome 8p12-p11.2 have been identified in approximately 90% of individuals with this syndrome; no other genes are known to be associated with Werner syndrome.[166,170,171,172,173] Inheritance of this gene is believed to be autosomal recessive. The product of the WRN gene is a multifunctional protein including a DNA exonuclease and an ATP-dependent DNA helicase belonging to the RecQ subfamily. This protein may play a role in processes such as DNA repair, recombination, replication, transcription, and combined DNA functions.[174,175,176,177,178,179,180,181,182] Telomere dysfunction has been associated with premature aging and cancer susceptibility. Other helicases with similar function are altered in other chromosomal instability syndromes, such as BLM in Bloom syndrome and RecQL4 in Rothmund-Thomson syndrome.
Deleterious mutations described in the WRN gene include all types of mutations; however the the 1136C?T mutation is the most common and is found in 20% to 25% of the Japanese and white populations.[184,185] In the Japanese population, a founder mutation (IVS 25-1G?C) is present in 60% of affected individuals.
Mutation in the WRN gene causes loss of nuclear localization of the gene product. Intracellular levels of the mRNA and protein associated with the mutated gene are also markedly decreased, compared with those of the wild-type. Half-lives of the mRNA and protein associated with the mutated gene are also shorter than those associated with the wild-type mRNA and protein.[185,187]