{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T12:43:34Z","timestamp":1793882614236,"version":"4.7.0"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,8,23]],"date-time":"2017-08-23T00:00:00Z","timestamp":1503446400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,8,23]],"date-time":"2017-08-23T00:00:00Z","timestamp":1503446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>SLC10A1<\/jats:italic> codes for the sodium-taurocholate cotransporting polypeptide (NTCP), which is a hepatocellular transporter for bile acids (BAs) and the receptor for hepatitis B and D viruses. NTCP is also a target of multiple drugs. We aimed to evaluate the medical consequences of the loss of function mutation p.Ser267Phe in <jats:italic>SLC10A1<\/jats:italic>. We identified eight individuals with homozygous p.Ser267Phe mutation in <jats:italic>SLC10A1<\/jats:italic> and followed up for 8\u201390 months. We compared their total serum BAs and 6 species of BAs with 170 wild-type and 107 heterozygous healthy individuals. We performed in-depth medical examinations and exome sequencing in the homozygous individuals. All homozygous individuals had persistent hypercholanemia (<jats:italic>P<\/jats:italic>\u2009=\u20095.8\u2009\u00d7\u200910<jats:sup>\u201329<\/jats:sup>). Exome sequencing excluded the involvement of other BA metabolism-associated genes in the hypercholanemia. Although asymptomatic, all individuals had low vitamin D levels. Of six adults that were subjected to bone mineral density analysis, three presented with osteoporosis\/osteopenia. Sex hormones and blood lipids were deviated in all subjects. Homozygosity of p.Ser267Phe in <jats:italic>SLC10A1<\/jats:italic> is associated with asymptomatic hypercholanemia. Individuals with homozygous p.Ser267Phe in <jats:italic>SLC10A1<\/jats:italic> are prone to vitamin D deficiency, deviated sex hormones and blood lipids. Surveillance of these parameters may also be needed in patients treated with drugs targeting NTCP.<\/jats:p>","DOI":"10.1038\/s41598-017-07012-2","type":"journal-article","created":{"date-parts":[[2017,8,17]],"date-time":"2017-08-17T13:21:24Z","timestamp":1502976084000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Homozygous p.Ser267Phe in SLC10A1 is associated with a new type of hypercholanemia and implications for personalized medicine"],"prefix":"10.1038","volume":"7","author":[{"given":"Ruihong","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuming","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qijun","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Newcombe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1975-1002","authenticated-orcid":false,"given":"Shuhua","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fucheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minlian","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaiqiu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruimin","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiping","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binghui","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihao","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danhua","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pak","family":"Sham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingnan","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick H.","family":"Maxwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-liang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,23]]},"reference":[{"key":"7012_CR1","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1002\/cphy.c120027","volume":"3","author":"JL Boyer","year":"2013","unstructured":"Boyer, J. L. Bile formation and secretion. Compr Physiol \n                           3, 1035\u20131078 (2013).","journal-title":"Compr Physiol"},{"key":"7012_CR2","doi-asserted-by":"publisher","first-page":"e00049","DOI":"10.7554\/eLife.00049","volume":"1","author":"H Yan","year":"2012","unstructured":"Yan, H. et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife \n                           1, e00049 (2012).","journal-title":"Elife"},{"key":"7012_CR3","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/s00424-013-1367-0","volume":"466","author":"MS Anwer","year":"2014","unstructured":"Anwer, M. S. & Stieger, B. Sodium-dependent bile salt transporters of the SLC10A transporter family: more than solute transporters. Pflugers Arch \n                           466, 77\u201389 (2014).","journal-title":"Pflugers Arch"},{"key":"7012_CR4","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1021\/mp300453k","volume":"10","author":"Z Dong","year":"2013","unstructured":"Dong, Z., Ekins, S. & Polli, J. E. Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP). Mol Pharm \n                           10, 1008\u20131019 (2013).","journal-title":"Mol Pharm"},{"key":"7012_CR5","doi-asserted-by":"crossref","unstructured":"Lapham, K. et al. Inhibition of Hepatobiliary Transport Activity by the Antibacterial Agent Fusidic Acid: Insights into Factors Contributing to Conjugated Hyperbilirubinemia\/Cholestasis. Chem Res Toxicol \n                           29 (2016).","DOI":"10.1021\/acs.chemrestox.6b00262"},{"key":"7012_CR6","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1016\/j.jhep.2016.04.016","volume":"65","author":"P Bogomolov","year":"2016","unstructured":"Bogomolov, P. et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib\/IIa study. J Hepatol \n                           65, 490\u2013498 (2016).","journal-title":"J Hepatol"},{"key":"7012_CR7","unstructured":"Qiu, Y. L. et al. Defects in MYO5B are associated with a spectrum of previously undiagnosed low gamma-glutamyltransferase cholestasis. Hepatology (2016)."},{"key":"7012_CR8","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1002\/hep.27240","volume":"61","author":"FM Vaz","year":"2015","unstructured":"Vaz, F. M. et al. Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype. Hepatology \n                           61, 260\u2013267 (2015).","journal-title":"Hepatology"},{"key":"7012_CR9","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1002\/hep.27294","volume":"61","author":"SJ Karpen","year":"2015","unstructured":"Karpen, S. J. & Dawson, P. A. Not all (bile acids) who wander are lost: the first report of a patient with an isolated NTCP defect. Hepatology \n                           61, 24\u201327 (2015).","journal-title":"Hepatology"},{"key":"7012_CR10","doi-asserted-by":"publisher","first-page":"7213","DOI":"10.1074\/jbc.M305782200","volume":"279","author":"RH Ho","year":"2004","unstructured":"Ho, R. H., Leake, B. F., Roberts, R. L., Lee, W. & Kim, R. B. Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition. J Biol Chem \n                           279, 7213\u20137222 (2004).","journal-title":"J Biol Chem"},{"key":"7012_CR11","doi-asserted-by":"publisher","first-page":"501","DOI":"10.3109\/00498254.2011.555567","volume":"41","author":"W Pan","year":"2011","unstructured":"Pan, W. et al. Genetic polymorphisms in Na+-taurocholate co-transporting polypeptide (NTCP) and ileal apical sodium-dependent bile acid transporter (ASBT) and ethnic comparisons of functional variants of NTCP among Asian populations. Xenobiotica \n                           41, 501\u2013510 (2011).","journal-title":"Xenobiotica"},{"key":"7012_CR12","doi-asserted-by":"publisher","first-page":"3273","DOI":"10.1128\/JVI.03478-13","volume":"88","author":"H Yan","year":"2014","unstructured":"Yan, H. et al. Viral entry of hepatitis B and D viruses and bile salts transportation share common molecular determinants on sodium taurocholate cotransporting polypeptide. J Virol \n                           88, 3273\u20133284 (2014).","journal-title":"J Virol"},{"key":"7012_CR13","doi-asserted-by":"crossref","first-page":"3294","DOI":"10.3892\/etm.2016.3752","volume":"12","author":"M Deng","year":"2016","unstructured":"Deng, M. et al. Clinical and molecular study of a pediatric patient with sodium taurocholate cotransporting polypeptide deficiency. Exp Ther Med \n                           12, 3294\u20133300 (2016).","journal-title":"Exp Ther Med"},{"key":"7012_CR14","unstructured":"Van Herpe, F. et al. NTCP deficiency and persistently raised bile salts: an adult case. J Inherit Metab Dis (0032017)."},{"key":"7012_CR15","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1186\/s12885-016-2257-6","volume":"16","author":"J Yang","year":"2016","unstructured":"Yang, J. et al. A genetic variant of the NTCP gene is associated with HBV infection status in a Chinese population. BMC Cancer \n                           16, 211 (2016).","journal-title":"BMC Cancer"},{"key":"7012_CR16","doi-asserted-by":"publisher","first-page":"1514","DOI":"10.1136\/gutjnl-2015-310686","volume":"65","author":"HH Hu","year":"2016","unstructured":"Hu, H. H. et al. The rs2296651 (S267F) variant on NTCP (SLC10A1) is inversely associated with chronic hepatitis B and progression to cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B. Gut \n                           65, 1514\u201321 (2016).","journal-title":"Gut"},{"key":"7012_CR17","doi-asserted-by":"publisher","first-page":"3920","DOI":"10.1016\/j.jchromb.2009.09.038","volume":"877","author":"M Scherer","year":"2009","unstructured":"Scherer, M., Gnewuch, C., Schmitz, G. & Liebisch, G. Rapid quantification of bile acids and their conjugates in serum by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci \n                           877, 3920\u20133925 (2009).","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"key":"7012_CR18","doi-asserted-by":"publisher","first-page":"1803","DOI":"10.1007\/s11095-007-9289-1","volume":"24","author":"WA Alrefai","year":"2007","unstructured":"Alrefai, W. A. & Gill, R. K. Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm Res \n                           24, 1803\u20131823 (2007).","journal-title":"Pharm Res"},{"key":"7012_CR19","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1002\/hep.27608","volume":"61","author":"L Peng","year":"2015","unstructured":"Peng, L. et al. The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B. Hepatology \n                           61, 1251\u20131260 (2015).","journal-title":"Hepatology"},{"key":"7012_CR20","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.ajhg.2015.05.005","volume":"97","author":"H Lou","year":"2015","unstructured":"Lou, H. et al. A 3.4-kb Copy-Number deletion near EPAS1 is significantly enriched in High-Altitude tibetans but absent from the denisovan sequence. Am J Hum Genet \n                           97, 54\u201366 (2015).","journal-title":"Am J Hum Genet"},{"key":"7012_CR21","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/ejhg.2013.111","volume":"22","author":"P Qin","year":"2014","unstructured":"Qin, P. et al. A panel of ancestry informative markers to estimate and correct potential effects of population stratification in Han Chinese. Eur J Hum Genet \n                           22, 248\u2013253 (2014).","journal-title":"Eur J Hum Genet"},{"key":"7012_CR22","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1056\/NEJMra070553","volume":"357","author":"MF Holick","year":"2007","unstructured":"Holick, M. F. Vitamin D deficiency. N Engl J Med \n                           357, 266\u2013281 (2007).","journal-title":"N Engl J Med"},{"key":"7012_CR23","first-page":"493","volume":"47","author":"H Li","year":"2009","unstructured":"Li, H., Ji, C. Y., Zong, X. N. & Zhang, Y. Q. [Body mass index growth curves for Chinese children and adolescents aged 0 to 18 years]. Zhonghua Er Ke Za Zhi \n                           47, 493\u2013498 (2009).","journal-title":"Zhonghua Er Ke Za Zhi"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-07012-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-07012-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-07012-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T09:18:07Z","timestamp":1671787087000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-07012-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,23]]},"references-count":23,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["7012"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-07012-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,23]]},"assertion":[{"value":"22 March 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 June 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 August 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"9214"}}