What are the genetic changes related to SLC4A1-associated distal renal tubular acidosis ?
Both the autosomal dominant and autosomal recessive forms of SLC4A1-associated distal renal tubular acidosis are caused by mutations in the SLC4A1 gene. This gene provides instructions for making the anion exchanger 1 (AE1) protein, which transports negatively charged atoms (anions) across cell membranes. Specifically, AE1 exchanges negatively charged atoms of chlorine (chloride ions) for negatively charged bicarbonate molecules (bicarbonate ions). The AE1 protein is found in the cell membrane of kidney cells and red blood cells. In kidney cells, the exchange of bicarbonate through AE1 allows acid to be released from the cell into the urine. In red blood cells, AE1 attaches to other proteins that make up the structural framework (the cytoskeleton) of the cells, helping to maintain their structure.  The SLC4A1 gene mutations involved in either form of SLC4A1-associated distal renal tubular acidosis lead to production of altered AE1 proteins that cannot get to the correct location in the cell membrane. In the autosomal dominant form of the condition, gene mutations affect only one copy of the SLC4A1 gene, and normal AE1 protein is produced from the other copy. However, the altered protein attaches to the normal protein and keeps it from getting to the correct location, leading to a severe reduction or absence of AE1 protein in the cell membrane. In autosomal recessive distal renal tubular acidosis, both copies of the SLC4A1 gene are mutated, so all of the protein produced from this gene is altered and not able to get to the correct location. Improper location or absence of AE1 in kidney cell membranes disrupts bicarbonate exchange, and as a result, acid cannot be released into the urine. Instead, the acid builds up in the blood in most affected individuals, leading to metabolic acidosis and the other features of complete distal renal tubular acidosis. It is not clear why some people develop metabolic acidosis and others do not. Researchers suggest that in individuals with incomplete distal renal tubular acidosis, another mechanism is able to help regulate blood acidity (pH) and keep metabolic acidosis from developing.  In red blood cells, interaction with a protein called glycophorin A can often help the altered AE1 protein get to the cell membrane where it can perform its function, which explains why most people with SLC4A1-associated distal renal tubular acidosis do not have blood cell abnormalities. However, some altered AE1 proteins cannot be helped by glycophorin A and are not found in the cell membrane. Without AE1, the red blood cells are unstable; breakdown of these abnormal red blood cells may lead to hemolytic anemia.  Some people have nonhereditary forms of distal renal tubular acidosis; these forms can be caused by immune system problems or other conditions that damage the kidneys. These individuals often have additional signs and symptoms related to the original condition.