| Co-Investigator(Kenkyū-buntansha) |
IIJIMA Mikio Kagoshima University, Faculty of Medicine, Research Associate, 医学部, 助手 (00305111)
SAHEKI Takeyori Kagoshima University, Faculty of Medicine, Professor, 医学部, 教授 (10056070)
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| Research Abstract |
Adult-onset type II citrullinemia (CTLN2) is characterized by a liver-specific deficiency of argininosuccinate synthetase (ASS), with is a rate-limiting enzyme of the urea cycle. Although the prognosis of CTLN2 is bad, liver transplantation is remarkably effective. Kobayashi at al. have discovered that CTLN2 is caused by mutations of the SLC25A13 gene on 7q21.3, with encodes a calcium-binding mitochondrial solute carrier protein, designated citrin (Nat Genet 22 : 159-163, 1999).
In the present study we found that the citrin deficiency causes not only CTLN2 but also neonatal hepatitis with intrahepatic cholestasis, named NICCD. So far, we have identified 18 including 5 known) SLC25A13 mutations in 129 CTLN2 and 108 NICCD patients, and for most frequent 9 mutations, established multiple DNA diagnosis methods using GeneScan/SNaPshot. DNA diagnosis revealed that the carrier frequency is 1/69 (homozygote frequency : 1/19,000) in the Japanese population. Citrin deficiency was thought to be restricted to Japan, but we found some cases in other country. In our preliminary screening study, we detected a similar carrier frequency (1/50-1/100) in East Asia. Most NICCD patients show symptoms, with ameliorate by 1 year of age. More Than 10 years or even several decades later, some patients develop severe CTLN2 with neuropsychiatric symptoms. Since we found that citrin and the isoform, aralar, localize in the mitochondrial inner membrane and function as aspartate glutamate carriers stimulated by calcium, the various symptoms of NICCD and CTLN2 may be understood through the defects of aspartate export from mitochondria to cytosol and of malate aspartate NADH shuttle. It is, however, still difficult to clarify the mechanism of hepatic defect of ASS protein in CTLN2. We generated two kinds of citrin-deficient mice and are now examining them to see whether they are suitable as animal models for NICCD and/or CTLN2.
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