Abstract
Mutations in SLC25A13 cause citrin deficiency, which has three phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) and adult-onset type 2 citrullinemia (CTLN2). The purpose of this study was to determine the mutation spectrum and the clinical and biochemical characteristics of citrin deficiency in Korean patients. Thirty-four patients were diagnosed with citrin deficiency based on mutations in SLC25A13, as verified by direct sequencing and long PCR screening of a large transposon insertion. A total of 66 alleles from 33 unrelated families of 34 patients with citrin deficiency (27 NICCD, 2 FTTDCD and 5 CTLN2) were retrospectively identified. The common pathogenic alleles were IVS16ins3kb (33%), c.851_854del (30%) and c.1177+1G>A (12%), and three novel variants were identified. Levels of citrulline, threonine, methionine, tyrosine and arginine and the threonine-to-serine ratio were higher in children with neonatal intrahepatic cholestasis caused by NICCD compared with that in patients with idiopathic neonatal hepatitis (INH). We concluded that Korean patients with citrin deficiency showed the highest frequency of the IVS16ins3kb mutation and that plasma amino-acid profiles can be used to differentiate between NICCD and INH.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Kobayashi, K., Sinasac, D. S., Iijima, M., Boright, A. P., Begum, L., Lee, J. R. et al. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat. Genet. 22, 159–163 (1999).
Ohura, T., Kobayashi, K., Tazawa, Y., Nishi, I., Abukawa, D., Sakamoto, O. et al. Neonatal presentation of adult-onset type II citrullinemia. Hum. Genet. 108, 87–90 (2001).
Tazawa, Y., Kobayashi, K., Ohura, T., Abukawa, D., Nishinomiya, F., Hosoda, Y. et al. Infantile cholestatic jaundice associated with adult-onset type II citrullinemia. J. Pediatr. 138, 735–740 (2001).
Saheki, T. & Kobayashi, K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J. Hum. Genet. 47, 333–341 (2002).
Kobayashi, K., Saheki, T. & Song, Y. Z. in GeneReviews(R) (eds Pagon, R. A., Adam, M. P., Ardinger, H. H., Wallace, S. E., Amemiya, A. & Bean, L. J. H.) (University of Washington, Seattle, WA, 1993).
Lu, Y. B., Kobayashi, K., Ushikai, M., Tabata, A., Iijima, M., Li, M. X. et al. Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency. J. Hum. Genet. 50, 338–346 (2005).
Tabata, A., Sheng, J. S., Ushikai, M., Song, Y. Z., Gao, H. Z., Lu, Y. B. 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).
Song, Y. Z., Zhang, Z. H., Lin, W. X., Zhao, X. J., Deng, M., Ma, Y. L. et al. SLC25A13 gene analysis in citrin deficiency: sixteen novel mutations in East Asian patients, and the mutation distribution in a large pediatric cohort in China. PLoS ONE 8, e74544 (2013).
Moyer, V., Freese, D. K., Whitington, P. F., Olson, A. D., Brewer, F., Colletti, R. B. et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J. Pediatr. Gastroenterol. Nutr. 39, 115–128 (2004).
Song, Y. Z., Deng, M., Chen, F. P., Wen, F., Guo, L., Cao, S. L. et al. Genotypic and phenotypic features of citrin deficiency: five-year experience in a Chinese pediatric center. Int. J. Mol. Med. 28, 33–40 (2011).
Dimmock, D., Maranda, B., Dionisi-Vici, C., Wang, J., Kleppe, S., Fiermonte, G. et al. Citrin deficiency, a perplexing global disorder. Mol. Genet. Metab. 96, 44–49 (2009).
Hutchin, T., Preece, M. A., Hendriksz, C., Chakrapani, A., McClelland, V., Okumura, F. et al. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) as a cause of liver disease in infants in the UK. J. Inherit. Metab. Dis. 32 (suppl 1), S151–S155 (2009).
Treepongkaruna, S., Jitraruch, S., Kodcharin, P., Charoenpipop, D., Suwannarat, P., Pienvichit, P. et al. Neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and SLC25A13 mutations among Thai infants. BMC Gastroenterol. 12, 141 (2012).
Gong, Z., Xu, W. J., Tian, G. L., Zhang, T. & Lv, Z. Neonatal intrahepatic cholestasis caused by citrin deficiency differentiated from biliary atresia. Eur. J. Pediatr. Surg. 26, 255–259 (2015).
Holecek, M. Ammonia and amino acid profiles in liver cirrhosis: effects of variables leading to hepatic encephalopathy. Nutrition 31, 14–20 (2015).
Kobayashi, K., Iijima, M., Ushikai, M., Ikeda, S. & Saheki, T. Citrin deficiency. J. Jpn Pediatr. Soc. 110, 1047–1059 (2006).
Kobayashi, K., Bang Lu, Y., Xian Li, M., Nishi, I., Hsiao, K. J. & Choeh, K. et al. Screening of nine SLC25A13 mutations: their frequency in patients with citrin deficiency and high carrier rates in Asian populations. Mol. Genet. Metab. 80, 356–359 (2003).
Acknowledgements
This study was supported by a grant from the National Research Foundation of Korea, funded by the Ministry of Education, Science and Technology (NRF-2016M3A9B4915706). We are grateful to the patients and their families for their participation in this study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Oh, S., Lee, B., Kim, GH. et al. Biochemical and molecular characteristics of citrin deficiency in Korean children. J Hum Genet 62, 305–307 (2017). https://doi.org/10.1038/jhg.2016.131
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2016.131
This article is cited by
-
Enhancing newborn screening sensitivity and specificity for missed NICCD using selected amino acids and acylcarnitines
Orphanet Journal of Rare Diseases (2025)
-
Neonatal intrahepatic cholestasis caused by citrin deficiency: clinical features, genetic characteristics, and treatment outcomes
BMC Gastroenterology (2025)
-
The mutation spectrum of SLC25A13 gene in citrin deficiency: identification of novel mutations in Vietnamese pediatric cohort with neonatal intrahepatic cholestasis
Journal of Human Genetics (2023)
