Pseudoxanthoma elasticum (Pseudoxanthoma elasticum, Groendblad-Strandberg syndrome, PXE) - Gen ABCC 6.
Pseudoxanthoma elasticum (Pseudoxanthoma elasticum) (PXE) is a hereditary progressive disease characterized by skin, eye injuries, and vascular due to accumulation of abnormal mineralized elastic fibers in these tissues (calcium deposits and other minerals). Cutaneous manifestations are the most characteristic of PXE and are often the first physical signs of disease development. These symptoms usually begin in childhood or adolescence and progress slowly unpredictably in adults. Accumulation calcified elastic fibers in the dermis causes typical skin lesions consisting of papules and plaques with yellowish small loss of elasticity. The lesions initially appear in the neck folds and areas like the armpit, antecubital fossa, English and periumbilical area. Papules are coalescing into larger plates causing the skin to lose elasticity, giving the appearance of premature aging. At this stage PXE diagnosis can be confirmed histologically showing skin lesions, with special stains, fragmented calcified elastic fibers. In the eyes they appear angioid streaks retinal, following fragmentation and calcification of the elastin - rich layer of the retina elastic component (Bruch 's membrane). These grooves cause subretinal neovascularization and hemorrhages, disciform leading to scarring and severe loss of central vision. As a result, people who suffer. Calcification of the internal elastic lamina of the arteries in average diameter can result in premature atherosclerosis, occlusive vascular changes that decrease blood flow of arms and legs resulting boxes intermittent claudication with exercise, or myocardial infarction. They can also cause rupture of blood vessels, especially in the gastrointestinal tract. In some patients can cause hypertension.
Involvement is due to mutations in the ABCC6 [ATP-Binding Cassette, subfamily C (CFTR / MRP) member 6] gene, located on the short arm of chromosome 16 (16p13.1). The ABCC6 gene belongs to a family of ABC (ATP-Binding Cassette), or ATP (ATPase Superfamily Tansporters), genes known genes and genes has 31 exons spanning over 71 kb. This gene encodes a protein (ATP-Binding Cassette, subfamily C, member 6) of 1,503 amino acid, currently known as MRP6 protein (multidrug resistance-associated protein 6), and also as ABCC6 protein. This protein has 17 transmembranbosos domains, and two intracellular nucleotide fixing folds (NFBs: Nucleotide Binding Folds), with three domains A, B and C. The C domain is critical split activate the ATP dependent transport through the cell membrane. The protein carries some substances through the cell membrane. The MRP6 / ABCC6 protein is found primarily in the liver and kidneys, with small amounts in the skin, stomach, blood vessels and eyes. Some studies suggest that the MRP6 / ABCC6 protein stimulates the release of adenosine triphosphate (ATP) from the cells by an unknown mechanism. This ATP rapidly decomposes adenosine monophosphate (AMP) and pyrophosphate. Pyrophosphate contributes to the control of calcification and mineralization in the body. Other studies suggest that the MRP6 / ABCC6 protein carries a substance involved in the degradation of ATP. It is believed that this unidentified substance helps prevent tissue mineralization. The protein is preferentially expressed in the liver and kidneys, and to a lesser extent, if any, in the tissues affected by Pseudoxanthoma elasticum.
They have been described at least 254 mutations in the ABCC6 gene in people with Pseudoxanthoma elasticum (PXE). The most frequent mutation, representing approximately 28% of cases, is a deletion of some exons ABCC6 (Ex23_29del) gene. The mutations described so far have been: missense mutations (168), and cutting mutations -splicing- junction (17), regulatory mutations (1), small deletions (31), small insertions (8), larger deletions (28) and complex rearrangements (1). Mutations in this gene result in the absence, or functional alteration of the MRP6 / ABCC6 protein, which causes impairment of transport of substances through the cell membrane, altering the normal cell activity. Although it is unknown how the calcification of elastic fibers and the characteristic features of Pseudoxanthoma elasticum occurs, this loss is likely to affect ATP release or transport of a substance that normally prevents mineralization. No MRP6 / ABCC6 functional, calcium and other minerals tend to accumulate on the elastic fibers of the skin, eyes, blood vessels and other tissues affected by PXE.
The disease has an autosomal recessive inheritance, which means that both copies (alleles) of the gene must be altered in each cell to disease expression. The parents of an affected individual have each a copy of the gene mutations but not show signs or symptoms of the disease. There are some cases reported in the scientific literature on cases of this disease mutations that appear in a single chromosomal allele, which has suggested that disease manifestations may occur in heterozygous patients. However, these are considered as pattern seudodominante inheritance that correspond to descendants of a homozygous parent (with disease and both alleles affected by the mutation) and a heterozygous parent (no disease, and one affected allele ), and where the offspring is heterozygous (one affected allele, but with disease). This implies a situation autosomal recessive simulating an autosomal dominant inheritance. This situation usually occurs more frequently in the X chromosome linked traits, but has also been observed in characters autosomal genes (genes not X - linked). This occurs when the dominant allele is lost by deletion or otherwise deficient mutation in the homologous allele, causing the heterozygosity of this locus is lost, so the individual is homozygous for that character, expressed as a recessive phenotype.
There are some descriptions in the scientific literature have suggested that heterozygous carriers may have increased risk of premature coronary artery disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with Pseudoxanthoma elasticum, by complete PCR amplification of the exons of the ABCC6 gene, 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).