Werner Syndrome, ..., (Werner syndrome) - Genes WRN and LMNA
Werner syndrome, also known as adult progeria, is a congenital disease characterized by premature aging adults between 20 and 30 years old. Those affected by Werner syndrome individuals tend to be short, with facies bird, wrinkled, juvenile cataracts, premature hair loss (around 20 years) and usually develop scleroderma with subcutaneous atrophy changes and epidermal thinning. These patients are also prevalent atherosclerosis, osteoporosis, diabetes mellitus type II (45-70%), hypogonadism and some cancers.
The main cause of death for people affected by Werner syndrome is cancer because they are more prone to developing tumors compared to the general population. The average life of those affected is 47 years. Tumors most often presented are soft tissue sarcomas and osteosarcomas (25-37% of total) parts, followed by malignant melanoma (17%) and thyroid carcinoma (16%). Other more minority have been breast carcinoma, hematologic malignancies and gastrointestinal tumors.
This process is generally due to mutations in the WRN gene, located on the short arm of chromosome 8 (8p12). WRN is a large gene, consisting of 35 exons, encoding a protein of 1432 amino acids predominantly localized in the nucleolus, which has helicase activity and DNA exonuclease. DNA helicases are involved in various aspects of DNA metabolism including transcription, replication and recombination. However, its principal function is to detect errors during DNA replication and repair and maintenance of telomere shortening whose aging- associated with playing a key role in maintaining genome integrity.
They have identified 60 mutations in the WRN gene responsible for Werner syndrome. Most mutations detected in the WRN gene associated with Werner syndrome produce truncation of the protein and cause the removal or alteration of nuclear localization signals in the C-terminal. Thus, regardless of where they occur, the WRN truncated proteins lacking nuclear localization signals can not enter the nucleus and are therefore null functionality. Moreover, the shortened protein is broken down more rapidly than normal protein Wener, reducing the amount of this protein in the cell. No normal Werner protein in the nucleus, DNA replication, repair, and transcription affected. Work is being done to determine how mutations in the WRN gene lead to signs and symptoms of Werner syndrome.
In a few cases (10-15%) in which there are some phenotypic differences, resulting in finding the WRN gene mutations it is negative. For a recent discovery is known that such cases due to genetic alterations autosomal dominant in another gene, LMNA, and are associated with the so - called "atypical Werner syndrome". LMNA, located in section 22 of the long arm of chromosome 1 (1q22), encoding the proteins of nuclear envelope sheet A and sheet C produced either by alternative splicing. These patients are characterized by an earlier than those with WRN gene abnormalities and more rapid progression of symptoms onset. In addition, patients of atypical Werner syndrome tend to have more severe disease progression and increased incidence of cardiomyopathy.
Werner's syndrome is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with Werner syndrome, by complete PCR amplification of exons WRN gene, and subsequent sequencing. If the negative result of the LMNA gene study is suggested by PCR amplification followed by direct sequencing if it were the atypical Werner syndrome.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).