Research Content

Project Professor Takeyori Saheki

Pathophysiology and treatment of citrin deficiency

Takeyori Saheki, Yuhki Fujimoto, Sumie Furuie

Citrin deficiency is a disease entity newly-established by Saheki and Kobayashi (13). Citrin is a product of a gene, SLC25A13, causative of adult-onset type II citrullinemia (CTLN2) (15), of which symptoms are consciousness disturbance and abnormal behavior caused by hyperammonemia (1). Following establishment of DNA diagnosis method, the same gene deficiency was found to cause neonatal cholestasis with multiple aminoacidemia (NICCD). These results leaded us to establish a disease entity, citrin deficiency (13). Citrin is a mitochondrial aspartate glutamate carrier (14), which plays a role not only in syntheses of protein, nucleotides and urea in the cytosol by supplying aspartate, but also in aerobic glycolysis by transporting NADH reducing equivalent from cytosol to mitochondria as a member of malate aspartate shuttle.

Up to recent several years ago, CTLN2 has been a severe disease resulting in early death because of inadequate treatment of hyperammonemia caused by CTLN2. This is because sugars, such as high carbohydrate diets, hyperosmotic glucose solution for infusion and glycerol for brain edema, are toxic for citrin deficiency since metabolism of sugars produces NADH in the cytosol, which inhibits urea synthesis without citrin, resulting in augmentation of hyperammonemia (1).

Therefore, it is important to establish novel therapeutics based on the pathogenesis and pathophysiology of the disease. For the purpose, we created Slc25a13 gene-knockout (Ctrn-KO) mice, which showed no symptoms, although urea synthesis was suppressed in the perfused liver of the mice (9). Therefore, we created the second model which was defective of not only citrin, but also mitochondrial glycerol-3-phosphate dehydrogenase (mGPD). The resultant Ctrn/mGPD double KO mice suffered from citrullinemia, hypoglycemia and hyperammonemia under fed conditions, recapitulating the features of human citrin deficiency (6). We have been clarifying the pathophysiology of the double-KO mice and developing novel therapeutics based on the pathophysiology of the novel mouse model (2, 3). So far, we have found that sodium pyruvate, protein, amino acids and MCT (medium-chain triglyceride) are effective.

On the other hand, we are now planning to find out modifier gene(s) which accelerate changes from NICCD to CTLN2 by using genome analysis such as exome analysis in collaboration with Prof. Dr. Ituro Inoue, National Institute of Genetics, Japan. The other projects of our group are to analyze pathophysiology of hepatocytes differentiated from iPS cells derived from citrin deficiency patients, and to establish a novel chemical diagnostics which can easily diagnose citrin deficiency without using DNA diagnosis. From these studies, we would like to diagnose citrin deficiency easily at early stage and establish how to prevent citrin deficiency subjects from CTLN2.

PAGE TOP