Renal hypouricemia - SLC2A9 or SLC22A12 gene.
Renal hypouricemia is a disease that reduces the concentration of uric acid in the blood. In the bloodstream, uric acid acts as an antioxidant, protecting cells from the damaging effects of free radicals. However, having too much uric acid in the body is toxic, so excess uric acid is eliminated from the body through the urine. People with renal hypouricemia have reduced concentrations of uric acid in the blood, because they eliminate an excessive amount of it in the urine. In many affected individuals, renal hypouricemia does not cause signs or symptoms. However, some people with this disease develop kidney problems. because an excessive amount of uric acid passes through the kidneys to be excreted in the urine, people with renal hypouricemia have an increased risk of developing nephrolithiasis. These uric acid stones can damage the kidneys and cause hematuria. Rarely, people with renal hypouricemia develop life-threatening renal failure.
This process is due to mutations in the SLC2A9 genes, located on the short arm of chromosome 4 (4p16.1) and SLC22A12, located on the long arm of chromosome 11 (11q13.1). These genes encode glucose transporter protein 9 (GLUT9) and transporter urate 1 (URAT1), respectively. These proteins are found in the kidneys, specifically in the proximal tubules. In the proximal tubules the necessary nutrients, water and other materials are reabsorbed to pass into the blood and substances that are not necessary in the urine are excreted. Inside the proximal tubules, both GLUT9 and URAT1 reabsorb the uric acid that passes into the bloodstream or release it in the urine, depending on the body´s needs. Most of the uric acid that seeps through the kidneys is reabsorbed into the bloodstream, while approximately 10% is released into the urine. GLUT9 protein also plays a role in the reabsorption and excretion of simple sugar glucose.
At least 13 mutations in the SLC2A9 gene and more than 30 mutations in the SLC22A12 gene have been identified in people with renal hypouricemia. These genetic changes lead to the coding of GLUT9 or URAT1 proteins with a reduced ability to reabsorb uric acid in the bloodstream. Instead, large amounts of uric acid are released into the urine. Although the specific cause of the signs and symptoms of renal hypouricemia is unclear, it is likely that when additional uric acid is produced during exercise and passes through the kidneys, it leads to tissue damage. Alternatively, without the antioxidant properties of uric acid, free radicals can cause damage to kidney tissues. Another possibility is that other substances are prevented from being reabsorbed together with uric acid, so the accumulation of these substances in the kidneys could lead to tissue damage. Individuals with mild renal hypouricemia or no symptoms are likely to have enough functional proteins that reabsorb a sufficient amount of uric acid into the bloodstream to prevent serious kidney problems.
This disease is inherited with an autosomal recessive pattern, that is, both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease. Sometimes, people with a mutation of the SLC2A9 gene in each cell have reduced uric acid concentrations but, in general, the concentrations are not as low as in people who have mutations in both copies of the gene, and often they do not cause any signs or symptoms. Rarely, people who carry a copy of the mutated gene will develop kidney stones of uric acid.
Tests performed in IVAMI: in IVAMI we detect mutations associated with renal hypouricemia, by complete PCR amplification of the exons of the SLC2A9 or SLC22A12 genes, respectively, and their subsequent sequencing.
Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).