2.1. SLC4A1-associated distal renal tubular acidosis

At least 18 SLC4A1 gene mutations have been found to cause SLC4A1-associated distal renal tubular acidosis, a kidney (renal) disorder that leads to the buildup of acid in the blood (metabolic acidosis). Some people with this condition also have blood cell abnormalities, such as hereditary spherocytosis, hereditary stomatocytosis, or Southeast Asian ovalocytosis (described below). The blood cell abnormalities can lead to hemolytic anemia, in which the abnormal red blood cells are prematurely broken down. SLC4A1 gene mutations cause both autosomal dominant and autosomal recessive forms of SLC4A1-associated distal renal tubular acidosis.

The SLC4A1 gene mutations involved in SLC4A1-associated distal renal tubular acidosis lead to production of altered AE1 proteins that are either stuck inside the cell or trafficked to the wrong side of the cell. 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 correct part of the cell membrane. In autosomal recessive SLC4A1-associated 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 trafficked correctly. 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, leading to metabolic acidosis. The inability to remove acid from the body also leads to the other features of distal renal tubular acidosis, including soft, weak bones; calcium deposits in the kidneys; and kidney stones.

Studies suggest that with the help of glycophorin A, the altered AE1 protein can often get to the cell membrane in red blood cells, 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 trafficked to red blood cell membranes. Without AE1, the red blood cells are unstable; breakdown of these abnormal red blood cells may lead to hemolytic anemia.

2.2. Other disorders

Mutations in the SLC4A1 gene can cause several blood disorders, including hereditary spherocytosis, hereditary stomatocytosis, and Southeast Asian ovalocytosis. Each of these conditions has an autosomal dominant inheritance pattern, which means a mutation in one copy of the SLC4A1 gene is sufficient to cause the disorder.

The mutations involved in hereditary spherocytosis lead to a reduction of AE1 protein, which results in abnormal red blood cells that are round and spherical rather than a flattened disk shape and are more fragile than usual. The abnormal cells are prematurely broken down, causing hemolytic anemia. Other features of hereditary spherocytosis, resulting from the breakdown of red blood cells, include yellowing of the skin and whites of the eyes (jaundice), gallstones, and an enlarged spleen (splenomegaly).

Hereditary stomatocytosis is characterized by abnormally shaped red blood cells that resemble a mouth or "stoma". This condition is caused by an abnormal AE1 protein that allows positively charged molecules of sodium (Na⁺) and potassium (K⁺) to leak out of the cell. As a result, the red blood cells are unstable and are broken down more quickly than usual, leading to hemolytic anemia and related features.

Southeast Asian ovalocytosis is a blood disorder most common in regions where malaria is prevalent, primarily Southeast Asian countries including Thailand and Malaysia. The mutation that causes this disorder, often referred to as the SAO mutation, deletes nine protein building blocks (amino acids) in the AE1 protein. This change leads to a reduction of AE1 on the surface of red blood cells; as a result, the cells are unusually rigid and oval-shaped. The abnormal cells typically do not cause any health problems in affected individuals. Research indicates that Southeast Asian ovalocytosis, which is caused by a mutation in one copy of the SLC4A1 gene, protects against severe neurological complications of malaria. However, having the SAO mutation in both copies of the gene is likely lethal before birth.

While a shortage of the AE1 protein in the cell membrane affects the structure of red blood cells in these blood disorders, researchers speculate that enough normal AE1 protein remains in kidney cells for anion exchange and acid release, so affected individuals do not develop distal renal tubular acidosis (described above).