Xeroderma pigmentosum (xeroderma pigmentosum) - Genes ERCC2, ERCC3, POLH, XPA and XPC.
Xeroderma pigmentosum (XP), is an inherited disorder characterized by extreme sensitivity to ultraviolet light (UV). This disorder primarily affects the eyes and skin areas exposed to sunlight. Some affected individuals also have problems related to the nervous system.
Signs of the disease usually appear in infancy or early childhood. Many affected children develop a severe sunburn after spending only a few minutes in the sun. At 2 years, almost all children with xeroderma pigmentosum hipercrómicas marches develop skin (freckles) in areas exposed to the sun. In affected individuals, exposure to sunlight often causes xeroderma and pigmentation. Eyes xeroderma pigmentosum people can be very sensitive to the sun 's UV rays. If the eyes are not protected from the sun, they can become irritated and manifest vascular congestion, and cornea can become cloudy. In some people, eyelashes and eyelids fall can be thin and abnormally rotated inward or outward. About 30 percent of those affected develop progressive neurological disorders, which may include hearing loss, poor coordination, difficulty walking, problems with movement, loss of intellectual function, difficulty swallowing and speaking, and convulsions.
Most people with xeroderma pigmentosum develop multiple skin cancers during their lifetime. Without adequate sun protection, about half of children will develop their first skin cancer at the age of 10 years. These cancers occur most often on the face, lips and eyelids, although it can also develop on the scalp, eyes and the tip of the tongue. These people have a higher risk of other cancers, including brain tumors.
This disease is caused by mutations in ERCC2, ERCC3, POLH, XPA and XPC genes involved in the repair of damaged DNA.
The ERCC2 genes located on the long arm of chromosome 19 (19q13.3) and ERCC3, located on the long arm of chromosome 2 (2q21), XPB and XPD encode proteins, respectively. These proteins are subunits of the complex TFIIH. This complex has two main functions: involved in the process of gene transcription, and help repair damaged DNA. MBAs proteins act together to initiate gene transcription. They have identified more than 24 mutations in the gene ERCC2 and a single mutation in ERCC3 in people with xeroderma pigmentosum. The mutation identified in the gene ERCC3 changes in the amino acid phenylalanine protein by amino acid serine at position 99 (Phe99Ser or F99S). Mutations in both genes, prevent the TFIIH complex repair damaged DNA effectively. As a result, abnormalities accumulate in the DNA, causing malfunctions of cells which eventually die or become cancerous. When the disease is caused by mutations in this gene often it is associated with progressive neurological disorders.
The POLH gene, located on the short arm of chromosome 6 (6p21.1), encodes a polymerases (pol eta), which are a group of enzymes important in the copy of genetic material of cells in preparation for cell division, playing a critical role in DNA repair. The main function of the polymerase eta, is to copy the DNA has been damaged, particularly ultraviolet rays of sunlight (UV). They have identified more than 30 mutations in the gene POLH, causing a variant of xeroderma pigmentosum (XP - V). Like other forms of xeroderma pigmentosum, XP-V is characterized by an increased sensitivity to UV rays of sunlight. However, this form of the disease is not usually associated with neurological disorders. Most mutations in the gene POLH prevent DNA polymerase eta encoding, which prevents cells copy the damaged DNA effectively. Without this mechanism, the errors resulting from exposure to UV accumulate in the genes that control cell growth and division. These errors make the cells grow too fast and uncontrolled. As a result, people with XP- V have a higher risk of developing skin cancer in areas where the skin is exposed to sunlight.
XPA genes located on the long arm of chromosome 9 (9q22.3), and XPC, located on the short arm of chromosome 3 (3p25.1), encode proteins involved in the repair of damaged DNA. One of the key mechanisms used by cells to repair DNA excision repair is the nucleotide (NER). As part of this repair mechanism, the XPA and XPC proteins help verify DNA damage repair and stabilize by. Aggregates these proteins bind to areas of damaged DNA, where they interact with many other proteins as part of a large complex. This complex proteins replace the damaged area with the correct DNA. They have identified at least 25 mutations in the XPA gene and over 40 mutations in the XPC xeroderma pigmentosum cause. Mutations result in a nonfunctional protein or greatly reduce the amount of this protein is encoded in the cells. A partial or complete loss of the protein prevents the cells to repair DNA damage normally. As a result, abnormalities accumulate in the DNA, causing the cells to malfunction and eventually become cancerous or die. When xeroderma pigmentosum is caused by mutations in the XPA gene, often associated with progressive neurological disorders.
This disease is inherited in an autosomal recessive pattern, that is, 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 xeroderma pigmentosum, by complete PCR amplification of the exons of the ERCC2, ERCC3, POLH, XPA and XPC genes, respectively, and subsequent sequencing.
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).