| Co-Investigator(Kenkyū-buntansha) |
SAHEKI Takeyori Tokushima Bunri University, Institute for Health Sciences, Professor, 健康科学研究所, 教授 (10056070)
LIJIMA Mikio Kagoshima University, Graduate School of Medical and Dental Sciences, Research Associate, 大学院医歯学総合研究科, 助手 (00305111)
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| Research Abstract |
Citrin deficiency is a newly-established disease entity that encompasses both cholestatic neonatal hepatitis (NICCD) and adult-onse: type II citrullinemia (CTLN2), and results from mutations in the SLC25A13 gene that encodes citrin. Citrin deficiency results in NICCD during the first few months of life, with symptoms usually self-resolving by the first year in most cases. Following an apparently healthy period that can last from one to several decades, some patients with citrin deficiency go on to develop severe CTLN2. From the function of citrin as a liver-type aspartate-glutamate carrier localized in the mitochondrial inner membrane, some of 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 CTLN2-onset.
In the present study, we identified near 20 novel SLC25A13 mutations and established their DNA diagnoses. Furth
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ermore, we also developed a novel diagnostic method to detect citrin protein in lymphocytes by using Western blot analysis. We have found the patients with citrin deficiency not only in Japan but also in other country. So far, we have diagnosed NICCD (203 Japanese, 40 Chinese, 6 Korean, 4 Vietnamese, 3 Caucasian, 3 Palestinian, 2 Jewish, 2 Israeli, 1 Pakistani) and CTLN2 (157 Japanese, 3 Chinese and 2 Korean) patients. DNA diagnosis revealed that the carrier frequency is 1,65 (homozygote frequency: 1/17,000) in the Japanese population. Our population analysis of 12 known mutations identified in Japanese patients detected many carriers in East Asia: the rates are 1/112 in Korea and 1/65 in China (Guangdong and Hunan: 1/40, Hong Kong: 1/48, Taiwan: 1/57), suggesting that over 100,000 East Asians are homozygotes of citrin deficiency. On the other hand, we generated citrin-KO (knockout) mice, but the mice failed to display features of human citrin deficiency. Based on the hypothesis that an enhanced glycerol phosphate shuttle activity in mouse liver compared to that in human can compensate for the loss of citrin function, we generated mice with a combined disruption of the genes for citrin and mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH). The resulting double-KO mice demonstrated citrullinemia, hyperammonemia that was further elevated by oral sucrose administration, hypoglycemia, and fatty liver; all features of human citrin deficiency (submitted to J Biol Chem). Less
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