Distribution and regional expression of citrin in human tissues, genetic abnormality and possible role in clinical features of type II citrullinemia

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Type II citrullinemia (CTLN2) is autosomal recessive disorder, characterized by adult-onset recurrent consciousness disturbance and/or abnormal behavior due to encephalopathy associated with hyperammonemia and severe brain edema. Histopathological study of CTLN2 patients shows severe liver-specific deficiency of argininosuccinate synthetase (ASS), which relates to ammonia metabolism in cytosole of hepatocytes. No mutations or abnormal mRNA expression in ASS gene have been found in this disorder. Mutations in SLC25A13 gene have been identified as genetic cause of the CTLN2. SLC25A13 gene encodes a mitochondrial solute carrier protein named citrin. Recent study showed that mutation of SLC25A13 also cause idiopathic neonatal hepatitis (NICCD). OBJECTIVE: To examine distribution and regional expression of citrin protein and mRNA in multiple human organs. METHODS: The hearts, kidneys, livers, pancreas, skeletal muscles, lungs and brains from 5 patients died with various diseases were examin … More ed. Detailed regional distributions were determined by immunohistochemistry with using polyclonal antibody to citrin and in situ hybridization. We also conducted western blotting in human control organs. RESULTS: On western blotting, only one band of 74 kDa was detected by the antibody to citrin predominantly in liver and kidney, moderately in pancreas and brain, slightly in lung, but not in heart and skeletal muscle. Immunohistochemistry using the antibody to citrin showed positive staining strongly in hepatocytes of liver tissues, epithelial cells of proximal and distal tubules, and podocyte in kidney tissues, moderately in centroacinar cells of pancreas tissues, astrocytes in brain tissues, and pneumocytes in lung tissues. In situ hybridization histochemistry revealed that mRNA of citrin was showed almost the same distribution in comparison with immunohistochemistry. CONCLUSIONS: Distributions of citrin protein and mRNA were limited in several organs. Citrin was greatly expressed in hepatocyte, indicating that dysfunction of this molecule might cause hyperammonic encephalopathy and fatty liver seen in this disorder. Our study also indicated that citrin dysfunction in astrocytes and centroacinar cells might plays a role of the promotion factor about encephalopathy and chronic pancreatitis in CTLN2. Less