{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:34:19Z","timestamp":1791408859948,"version":"4.3.3"},"reference-count":100,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T00:00:00Z","timestamp":1745280000000},"content-version":"vor","delay-in-days":111,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020026","name":"Citrin Foundation","doi-asserted-by":"publisher","award":["G115743"],"award-info":[{"award-number":["G115743"]}],"id":[{"id":"10.13039\/501100020026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020026","name":"Citrin Foundation","doi-asserted-by":"publisher","award":["RG22005"],"award-info":[{"award-number":["RG22005"]}],"id":[{"id":"10.13039\/501100020026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["CRSII-222794"],"award-info":[{"award-number":["CRSII-222794"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["320030_207965"],"award-info":[{"award-number":["320030_207965"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K07316"],"award-info":[{"award-number":["23K07316"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","award":["23FC1033"],"award-info":[{"award-number":["23FC1033"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>Citrin deficiency (CD) is an autosomal recessive disorder caused by the absence or dysfunction of the mitochondrial transporter citrin, resulting from mutations in <jats:italic>SLC25A13<\/jats:italic>. The disease presents with age\u2010dependent clinical manifestations: neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia by CD (FTTDCD), and an adult\u2010onset form (formerly called Type II citrullinemia, CTLN2, recently renamed to \u201cadolescent and adult citrin deficiency,\u201d AACD). We performed this study to compile known genotypes found in CD patients and investigate their impact on the clinical course. Through a nationwide survey in Japan as well as a literature review, we collected information regarding 68 genetic variants of a total of 345 patients with CD (285 NICCD, 19 post\u2010NICCD, and 41 AACD). In this cohort, the pathogenic variants, arising from nonsense, insertion\/deletion, and splice site mutations, are expected to have severe functional or biogenesis defects. Of 82 alleles in patients with AACD, the two most common variants, c.852_855del and c.1177+1G&gt;A, accounted for 25 alleles (30.5%) and 15 alleles (18.3%), respectively. The c.852_855del variant, even when present as part of compound heterozygosity, often presented with hyperammonemia (\u2265\u2009180\u2009\u03bcmol\/L), cognitive impairment, short stature (&lt; \u20102SD), liver cirrhosis, and pancreatitis, with some patients requiring liver transplantation. In conclusion, certain <jats:italic>SLC25A13<\/jats:italic> genotypes are particularly frequent, especially those that result in severely truncated citrin proteins with often a significant impact on the clinical outcome of the patient. The most prevalent variant is c.852_855del, which was found in 42% (128\/304) of NICCD\/post\u2010NICCD cases and 49% (20\/41) of AACD patients.<\/jats:p>","DOI":"10.1155\/humu\/9326326","type":"journal-article","created":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T09:54:02Z","timestamp":1745315642000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Deciphering the Mutational Background in Citrin Deficiency Through a Nationwide Study in Japan and Literature Review"],"prefix":"10.1155","volume":"2025","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1328-6696","authenticated-orcid":false,"given":"Jun","family":"Kido","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1345-6459","authenticated-orcid":false,"given":"Keishin","family":"Sugawara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4263-8905","authenticated-orcid":false,"given":"Sotiria","family":"Tavoulari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9097-1991","authenticated-orcid":false,"given":"Georgios","family":"Makris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"R\u00fcfenacht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4903-2428","authenticated-orcid":false,"given":"Kimitoshi","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0610-4500","authenticated-orcid":false,"given":"Edmund R. S.","family":"Kunji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0635-091X","authenticated-orcid":false,"given":"Johannes","family":"H\u00e4berle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,22]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/9667"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004390000448"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2011.653"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1067\/mpd.2001.113264"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12722"},{"key":"e_1_2_12_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/nu14173605"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-6903-6_9"},{"key":"e_1_2_12_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0009-8981(82)90230-3"},{"key":"e_1_2_12_9_2","first-page":"667","article-title":"Messenger-RNA Coding for Argininosuccinate Synthetase in Citrullinemia","volume":"38","author":"Kobayashi K.","year":"1986","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_12_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.18.5060"},{"key":"e_1_2_12_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(67)90556-6"},{"key":"e_1_2_12_12_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00009.2020"},{"key":"e_1_2_12_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6491"},{"key":"e_1_2_12_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2019.06.004"},{"key":"e_1_2_12_15_2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.71.5.663"},{"key":"e_1_2_12_16_2","doi-asserted-by":"publisher","DOI":"10.3390\/nu12113313"},{"key":"e_1_2_12_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1096-7192(03)00140-9"},{"key":"e_1_2_12_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10038-005-0262-8"},{"key":"e_1_2_12_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2021.104145"},{"key":"e_1_2_12_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0089267"},{"key":"e_1_2_12_21_2","doi-asserted-by":"publisher","DOI":"10.21037\/tp-21-58"},{"key":"e_1_2_12_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0008-6"},{"key":"e_1_2_12_23_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v19.i43.7735"},{"key":"e_1_2_12_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10022"},{"key":"e_1_2_12_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2008.10.007"},{"key":"e_1_2_12_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2011.08.022"},{"key":"e_1_2_12_27_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12887-020-02409-x"},{"key":"e_1_2_12_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-009-1116-x"},{"key":"e_1_2_12_29_2","first-page":"112","article-title":"Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD) in a European Patient","volume":"29","author":"Hutchin T.","year":"2006","journal-title":"Journal of Inherited Metabolic Disease"},{"key":"e_1_2_12_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinre.2020.101595"},{"key":"e_1_2_12_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.06.011"},{"key":"e_1_2_12_32_2","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2008.103721"},{"key":"e_1_2_12_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2011.12.024"},{"key":"e_1_2_12_34_2","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.20.6.809"},{"key":"e_1_2_12_35_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004390000430"},{"key":"e_1_2_12_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12483"},{"key":"e_1_2_12_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10038-008-0282-2"},{"key":"e_1_2_12_38_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22981"},{"key":"e_1_2_12_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1153"},{"key":"e_1_2_12_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_12_41_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.176601"},{"key":"e_1_2_12_42_2","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2011_42"},{"key":"e_1_2_12_43_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12887-021-02717-w"},{"key":"e_1_2_12_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2005.06.009"},{"key":"e_1_2_12_45_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2014-4172"},{"key":"e_1_2_12_46_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-002-1045-2"},{"key":"e_1_2_12_47_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12887-020-02349-6"},{"key":"e_1_2_12_48_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2019.01108"},{"key":"e_1_2_12_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2012.06.012"},{"key":"e_1_2_12_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12887-020-02372-7"},{"key":"e_1_2_12_51_2","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2022-0616"},{"key":"e_1_2_12_52_2","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2014-0278"},{"key":"e_1_2_12_53_2","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2023.1103877"},{"key":"e_1_2_12_54_2","first-page":"92","article-title":"Clinic Analysis on 4 Infantile Citrin Deficiency Cases","volume":"26","author":"Wang X. X.","year":"2021","journal-title":"Hong Kong Journal of Paediatrics"},{"key":"e_1_2_12_55_2","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2014.1929"},{"key":"e_1_2_12_56_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12887-019-1751-9"},{"key":"e_1_2_12_57_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v21.i23.7331"},{"key":"e_1_2_12_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2012.09.049"},{"key":"e_1_2_12_59_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.19901"},{"key":"e_1_2_12_60_2","doi-asserted-by":"publisher","DOI":"10.1620\/tjem.233.275"},{"key":"e_1_2_12_61_2","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/4124263"},{"key":"e_1_2_12_62_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-006-0250-y"},{"key":"e_1_2_12_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2010.11.027"},{"key":"e_1_2_12_64_2","article-title":"Identification of a Novel Mutation in a Taiwanese Patient With Citrin Deficiency","volume":"29","author":"Sheng J. S.","year":"2006","journal-title":"Journal of Inherited Metabolic Disease"},{"key":"e_1_2_12_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2005.12.020"},{"key":"e_1_2_12_66_2","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000028954"},{"key":"e_1_2_12_67_2","doi-asserted-by":"publisher","DOI":"10.3346\/jkms.2007.22.6.952"},{"key":"e_1_2_12_68_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-010-9248-6"},{"key":"e_1_2_12_69_2","first-page":"53","article-title":"Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD) in Three Malay Children","volume":"32","author":"Ngu H. L.","year":"2010","journal-title":"The Malaysian Journal of Pathology"},{"key":"e_1_2_12_70_2","first-page":"E12","article-title":"Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency in Two Malaysian Siblings: Outcome at One Year of Life","volume":"51","author":"Thong M. K.","year":"2010","journal-title":"Singapore Medical Journal"},{"key":"e_1_2_12_71_2","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2019-0377"},{"key":"e_1_2_12_72_2","doi-asserted-by":"publisher","DOI":"10.24953\/turkjped.2017.03.012"},{"key":"e_1_2_12_73_2","doi-asserted-by":"publisher","DOI":"10.1542\/pir.2019-0001"},{"key":"e_1_2_12_74_2","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.49.2712"},{"key":"e_1_2_12_75_2","doi-asserted-by":"publisher","DOI":"10.2147\/TACG.S162084"},{"key":"e_1_2_12_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2013.12.002"},{"key":"e_1_2_12_77_2","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.12170"},{"key":"e_1_2_12_78_2","doi-asserted-by":"publisher","DOI":"10.1620\/tjem.240.323"},{"key":"e_1_2_12_79_2","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.51.7644"},{"key":"e_1_2_12_80_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1872-034X.2012.01098.x"},{"key":"e_1_2_12_81_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12328-019-01083-6"},{"key":"e_1_2_12_82_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2020.108159"},{"key":"e_1_2_12_83_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1872-034X.2012.00992.x"},{"key":"e_1_2_12_84_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clineuro.2012.12.027"},{"key":"e_1_2_12_85_2","doi-asserted-by":"publisher","DOI":"10.4103\/aian.aian_175_23"},{"key":"e_1_2_12_86_2","doi-asserted-by":"publisher","DOI":"10.4103\/0028-3886.156285"},{"key":"e_1_2_12_87_2","doi-asserted-by":"publisher","DOI":"10.1515\/med-2021-0235"},{"key":"e_1_2_12_88_2","first-page":"410","article-title":"Hyperammonaemic Encephalopathy in an Adult Patient With Citrin Deficiency Associated With a Novel Mutation","volume":"17","author":"Ng Y. W.","year":"2011","journal-title":"Hong Kong Medical Journal"},{"key":"e_1_2_12_89_2","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2016.3298"},{"key":"e_1_2_12_90_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0929-6646(09)60274-6"},{"key":"e_1_2_12_91_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2018.05.076"},{"key":"e_1_2_12_92_2","doi-asserted-by":"publisher","DOI":"10.1111\/pcn.12253"},{"key":"e_1_2_12_93_2","first-page":"1024","article-title":"A Search for the Primary Abnormality in Adult-Onset Type II Citrullinemia","volume":"53","author":"Kobayashi K.","year":"1993","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_12_94_2","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-022-01112-2"},{"key":"e_1_2_12_95_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep29732"},{"key":"e_1_2_12_96_2","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2016.131"},{"key":"e_1_2_12_97_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2022.05.002"},{"key":"e_1_2_12_98_2","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12294"},{"key":"e_1_2_12_99_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom10081100"},{"key":"e_1_2_12_100_2","first-page":"1543","article-title":"Molecular Basis of Citrin Deficiency","volume":"76","author":"Kobayashi K.","year":"2004","journal-title":"Seikagaku"}],"container-title":["Human Mutation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/humu\/9326326","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T09:54:05Z","timestamp":1745315645000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/humu\/9326326"}},"subtitle":[],"editor":[{"given":"George P.","family":"Patrinos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,1]]},"references-count":100,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["10.1155\/humu\/9326326"],"URL":"https:\/\/doi.org\/10.1155\/humu\/9326326","archive":["Portico"],"relation":{},"ISSN":["1059-7794","1098-1004"],"issn-type":[{"value":"1059-7794","type":"print"},{"value":"1098-1004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1]]},"assertion":[{"value":"2024-03-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"9326326"}}