Pathogenesis of adult-onset type II citrullinemia caused by deficiency of citrin, a mitochondrial solute carrier protein: Tissue and subcellular localization of citrin

Adult-onset type II citrullinemia (CTLN2) is characterized by a liver-specific deficiency of urea cycle enzyme, ASS, and is caused by mutations in SLC25A13 that encodes a mitochondrial solute carrier protein, citrin. Citrin is located mainly in the liver, and also in the kidney and heart of mice. Citrin expression changes during development in the liver, kidney and small intestine like ASS, but the change in citrin mRNA levels is less than ASS. In the liver, hepatocytes are the only cells which contain citrin and ASS, and they contain no aralar, an analogue of citrin. Although ASS together with citrin and aralar was expressed mainly in the early proximal tubular cells, citrin and aralar were highly expressed in the middle proximal tubular cells where ASS was much lower. These results suggest that citrin plays a role in broader functions in addition to urea and arginine synthesis, and that loss of citrin causes a decrease in ASS in hepatocytes, but not in the kidney, probably because the citrin analogue, aralar, may compensate for loss of citrin in the kidney. There must be some other mechanisms for the decrease of ASS in hepatocytes because ASS and citrin are located in the cytosol and in the mitochondrial inner membrane, respectively.