Abstract
Deficiency of citrin, liver-type mitochondrial aspartate-glutamate carrier, is an autosomal recessive disorder caused by mutations of the SLC25A13 gene on chromosome 7q21.3 and has two phenotypes: neonatal intrahepatic cholestatic hepatitis (NICCD) and adult-onset type II citrullinemia (CTLN2). So far, we have described 19 SLC25A13 mutations. Here, we report 13 novel SLC25A13 mutations (one insertion, two deletion, three splice site, two nonsense, and five missense) in patients with citrin deficiency from Japan, Israel, UK, and Czech Republic. Only R360X was detected in both Japanese and Caucasian. IVS16ins3kb identified in a Japanese CTLN2 family seems to be a retrotransposal insertion, as the inserted sequence (2,667-nt) showed an antisense strand of processed complementary DNA (cDNA) from a gene on chromosome 6 (C6orf68), and the repetitive sequence (17-nt) derived from SLC25A13 was found at both ends of the insert. All together, 30 different mutations found in 334 Japanese, 47 Chinese, 11 Korean, four Vietnamese and seven non-East Asian families have been summarized. In Japan, IVS16ins3kb was relatively frequent in 22 families, in addition to known mutations IVS11 + 1G > A, 851del4, IVS13 + 1G > A, and S225X in 189, 173, 48 and 30 families, respectively; 851del4 and IVS16ins3kb were found in all East Asian patients tested, suggesting that these mutations may have occurred very early in some area of East Asia.
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Acknowledgments
We are grateful to the patients and their families as well as to the following physicians who provided samples and clinical information relating to the analysis of SLC25A13 mutations: Y. Takei, M. Yazaki and S. Ikeda (Shinshu University), T. Tana (Ryukyu University), E. Hashimoto (Tokyo Women’s Medical University), N. Onoda (Shuwa General Hospital), T. Kobayashi (Jichi Medical University), K. Hosoki (Mie General Medical Center), Y. Hasegawa (Kiyose Children’s Hospital), O. Elpeleg (Shaare Zedek Medical Center), E. Pospisilova (Charles University), and T. Hutchin (Birmingham Children’s Hospital). We also thank T. Yasuda, N. Yamaguchi, L. Begum, M.A. Jalil, and M. Horiuchi for technical assistance, and M. Gore for editorial assistance (Kagoshima University). This study was supported in part by Grants-in-Aid for Scientific Research (B: Nos. 16390100 and 19390096) and for Asia-Africa Scientific Platform Program from the Japan Society for the Promotion of Science, and by a Grant for Child Health and Development (17-2) from the Ministry of Health, Labour and Welfare in Japan.
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Tabata, A., Sheng, JS., Ushikai, M. et al. Identification of 13 novel mutations including a retrotransposal insertion in SLC25A13 gene and frequency of 30 mutations found in patients with citrin deficiency. J Hum Genet 53, 534–545 (2008). https://doi.org/10.1007/s10038-008-0282-2
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DOI: https://doi.org/10.1007/s10038-008-0282-2
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