{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T08:13:26Z","timestamp":1768724006618,"version":"3.49.0"},"reference-count":34,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2020YFA0804000"],"award-info":[{"award-number":["2020YFA0804000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The pathogenicity of cholestatic liver diseases (CLDs) remains insufficiently characterized, hindering definitive diagnosis and timely treatment. The aim of this study was to improve the pathogenicity prediction of novel bile acid (BA) transporter variants in patients with CLDs. We analyzed the clinical characteristics and genetic profiles of a CLD cohort (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200957) using multiple in silico tools and in\u00a0vitro functional assays. We identified 78 unique variants in four BA transporter genes. The predominant defects were associated with\n                    <jats:italic>ABCC2<\/jats:italic>\n                    (57\/78, 73.1%), with the most frequent being missense variants (39\/78, 50.0%). Using in silico tools, we identified 47 novel variants: 12 mis\u2010splicing, 21 deleterious missense, and 23 with altered protein stability. Of the 34 novel variants in\n                    <jats:italic>ABCC2<\/jats:italic>\n                    identified through in\u00a0vitro functional assays, seven incurred aberrant splicing, 11 missense variants resulted in MRP2 reduction, 9 missense variants resulted in abnormal N\u2010glycosylation, 18 variants altered MRP2 localization, and 26 variants reduced organic anion transport activity. These findings indicate that a multidisciplinary approach, integrating bioinformatics and experimental data, significantly enhances the accuracy of genetic\u2010based CLD diagnosis. It serves as a foundational study for BA transport variants pathogenicity reclassification and expands the mutation spectrum of CLDs in China.\n                  <\/jats:p>","DOI":"10.1111\/cge.14704","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T00:37:54Z","timestamp":1736815074000},"page":"3-13","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Functional Characterization and In Silico Prediction Tools Improve the Pathogenicity Prediction of Novel Bile Acid Transporter Variants"],"prefix":"10.1111","volume":"108","author":[{"given":"Ziyue","family":"Peng","sequence":"first","affiliation":[{"name":"Human Molecular Genetics Group, National Health Commission (NHC) Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University  Harbin China"},{"name":"Department of Pediatrics The Second Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Group, National Health Commission (NHC) Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University  Harbin China"},{"name":"College of Bioinformatics Science and Technology Harbin Medical University  Harbin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Group, National Health Commission (NHC) Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University  Harbin China"},{"name":"Department of Child and Adolescent Health, School of Public Health Harbin Medical University  Harbin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaqiong","family":"Ren","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Group, National Health Commission (NHC) Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University  Harbin China"},{"name":"McKusick\u2010Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Science and Peking Union Medical College  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhuan","family":"Meng","sequence":"additional","affiliation":[{"name":"KingMed School of Laboratory Medicine Guangzhou Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liwei","family":"Sun","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Group, National Health Commission (NHC) Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University  Harbin China"},{"name":"McKusick\u2010Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Science and Peking Union Medical College  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zitong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Group, National Health Commission (NHC) Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University  Harbin China"},{"name":"Department of Medical Genetics, College of Basic Medical Sciences Harbin Medical University  Harbin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Song","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Group, National Health Commission (NHC) Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University  Harbin China"},{"name":"Department of Pediatrics The Second Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Xia","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Group, National Health Commission (NHC) Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University  Harbin China"},{"name":"Department of Pediatrics The Second Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Shi","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Group, National Health Commission (NHC) Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University  Harbin China"},{"name":"Department of Medical Genetics, College of Basic Medical Sciences Harbin Medical University  Harbin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shihui","family":"Yu","sequence":"additional","affiliation":[{"name":"KingMed School of Laboratory Medicine Guangzhou Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Group, National Health Commission (NHC) Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University  Harbin China"},{"name":"College of Bioinformatics Science and Technology Harbin Medical University  Harbin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Group, National Health Commission (NHC) Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University  Harbin China"},{"name":"Department of Pediatrics The Second Affiliated Hospital of Harbin Medical University  Harbin China"},{"name":"Department of Child and Adolescent Health, School of Public Health Harbin Medical University  Harbin China"},{"name":"McKusick\u2010Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Science and Peking Union Medical College  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,1,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32437"},{"issue":"12","key":"e_1_2_10_3_1","first-page":"1075","article-title":"Guidelines on the Management of Cholestasis Liver Diseases (2021)","volume":"60","author":"Chinese Society of Hepatology","year":"2021","journal-title":"Zhonghua Nei Ke Za 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