Dent types 1 and 2, disease ... (Dent disease types 1 and 2) - Genes CLCN5 and OCRL
Dent's disease is a chronic renal disease due to alterations in the proximal renal tubules that occurs almost exclusively in males. Signs and symptoms of this disease appear in early childhood and worsen over time. The most common sign of Dent's disease is an elevated tubular proteinuria. Other common signs include hypercalciuria, nephrocalcinosis and nephrolithiasis. Kidney stones may cause abdominal pain and hematuria. In most affected individuals, the abnormal function of the proximal tubule leads to kidney at the beginning or mid-adulthood failure. Some people with the disease may develop rickets Dent, produced as a result of decreased concentrations of vitamin D and certain minerals such as calcium, blood. Rickets can be associated with the weakening and softening of the bones, bone pain, bowed legs and difficulty walking.
They described two forms of the disease Dent differentiated by their genetic cause and the pattern of signs and symptoms. Both forms of Dent's disease (type 1 and type 2), having the characteristics described previously, but Dent disease type 2 may also be associated with non-renal function abnormalities. These additional signs and symptoms include mild mental retardation, hypotonia and sub - clinical cataract because it does not affect vision. It is considered that the disease is type 2 Dent a slight variation of a similar process called Lowe syndrome.
Dent's disease may be due to mutations in CLCN5 and OCRL genes, located on the short arm of chromosome X (Xp11.23) and the short arm of chromosome X (Xq25), respectively. Mutations in the gene result CLCN5 Dent's disease type 1, which represents about 60% of all cases. Mutations in the gene are responsible OCRL type 2, which accounts for about 15% of all cases. In the remaining 25% of cases, the genetic cause of the disease is unknown. The proteins encoded from the CLCN5 and OCRL genes, play essential roles for normal renal function, particularly the function of the proximal renal tubules. These tubules reabsorb help nutrients, water and other materials filtered in glomeruli.
The gene encodes CLCN5 CLC-5 protein that transports ions through cell membranes. Specifically, it acts exchanging chloride ions, protons or hydrogen ions, so it is an exchanger H + / Cl -. CLC-5 is found mainly in the kidneys, particularly in the proximal renal tubules. Inside the cells of the proximal tubule, CLC-5 is in the endosomes, which are responsible for transporting proteins and other molecules into cells. CLC-5 transports hydrogen ions and chloride ions, which helps to maintain proper pH. Endosomal pH levels must be strictly regulated so that cells of the proximal tubule function properly.
150 have been identified mutations in the gene responsible CLCN5 Dent disease type 1. Most mutations result in the synthesis of a nonfunctional protein CLC-5 or inhibit encoding any protein. A loss of CLC-5 alters the regulation of endosomal pH, disrupting the overall function of the proximal tubule cells and prevents reabsorption of proteins and other materials into the bloodstream, resulting in tubular proteinuria. Failure reabsorption of calcium and other nutrients in the bloodstream can cause bone defects, kidney stones and other health problems related disease Dent 1. Ultimately, the abnormal function of the proximal tubule leads to kidney failure most affected individuals.
The OCRL gene encodes an enzyme which is present in cells throughout the body. This enzyme is part of a group enzymes that modify the membrane phospholipid molecules. Specifically enzyme regulates OCRL concentrations phospholipid phosphatidylinositol 4,5-bisphosphate membrane. This enzyme is found in several areas within the cells, concentrating on the trans-Golgi, complex network ordering proteins and other molecules and sends them to their destinations in or outside the cell. The OCRL enzyme is also found in endosomes cell surface to transport the proteins and other molecules to their destinations within the cell. By controlling the concentration of phosphatidylinositol 4,5-bisphosphate, the OCRL enzyme helps regulate the transport of certain substances to and from the cell membrane, and chemical signaling between cells. The enzyme may also participate in the regulation of the actin cytoskeleton, involved in the determination of cell shape and allowing the cells to move. Some research suggests that OCRL enzyme is found in the primary cilia, involved in signaling pathways that transmit information between cells. Studies suggest that OCRL enzyme may play a role in the formation, function and maintenance of cilia.
They have been described at least 20 mutations in the gene responsible OCRL Dent's disease type 2. These genetic alterations reduce or eliminate the function of the enzyme OCRL. These changes alter the transport of certain molecules as well as regulation of the actin cytoskeleton. They can also affect cellular signaling by altering the structure or function of the cilia. Disruption of these important cellular activities are likely to impair kidney function, resulting in proteinuria, kidney stones and ultimately kidney failure. However, it is not clear how the loss of the enzyme OCRL contributes to other signs and symptoms of this condition. OCRL because the enzyme is present throughout the body, it is unclear why Dent disease type 2 primarily affects the kidneys and, to a lesser extent, brain, eyes and other tissues. Other enzymes may be able to compensate for the defective enzyme OCRL in unaffected tissues.
Dent's disease is inherited in a recessive X - linked pattern CLCN5 and OCRL The genes are located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), an altered gene copy in each cell is sufficient to express the disease. In women (who have two X chromosomes), the mutation should occur in both copies of the gene to express the process. Because it is unlikely that women have two altered copies of this gene, males are affected by X - linked recessive disorders much more frequently than women. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome. In X - linked recessive inheritance, a woman with a mutated copy of the gene in each cell is called a carrier, because it can transmit the altered gene, but not usually develop signs and / or symptoms of the disease. However, some women who carry a mutation in the gene CLCN5 or OCRL gene have some minor features of Dent's disease, proteinuria and hypercalciuria. Other serious problems are rare in female carriers.
Tests in IVAMI: in IVAMI perform detection of mutations associated with disease Dent, by complete PCR amplification of the exons of CLCN5 and OCRL 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).