{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T05:48:46Z","timestamp":1775886526128,"version":"3.50.1"},"reference-count":31,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R37NS054791"],"award-info":[{"award-number":["R37NS054791"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>\n                      Cholestatic pruritus is a debilitating symptom in paediatric liver disease with a complex and poorly understood pathogenesis. Recent evidence implicates the Mas\u2010related G protein\u2010coupled receptor X4 (MRGPRX4)\u2014a bile acid receptor expressed in human dorsal root ganglia\u2014as a potential mediator of itch signalling. Although\n                      <jats:italic>MRGPRX4<\/jats:italic>\n                      harbours multiple single nucleotide variants (SNVs), their role in modulating cholestatic pruritus remains unexplored.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted a case\u2013control study at a single paediatric tertiary care center, enrolling patients with Alagille syndrome, Progressive Familial Intrahepatic Cholestasis (PFIC), biliary atresia, and Primary Sclerosing Cholangitis (PSC). Cases were defined as individuals with a history of pruritus; controls had no reported pruritus. Clinical data included peak total and fractionated bile acid levels. Targeted sequencing of the\n                      <jats:italic>MRGPRX4<\/jats:italic>\n                      coding region was performed to evaluate associations between SNVs and pruritus status.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 36 participants (17 cases, 19 controls), all harboured at least one coding\u2010region SNV in\n                      <jats:italic>MRGPRX4<\/jats:italic>\n                      . Eleven unique SNVs were identified, with recurrent variants at positions p.Phe8Leu, p.Asn25Lys, p.Val47Val, p.Tyr54Cys, p.Ala182Val, and p.Tyr215Tyr. While no single SNV was significantly associated with pruritus overall, the co\u2010occurring Phe8Leu, Asn25Lys, and Tyr215Tyr variants are less frequent in patients with pruritus, and a rare Lys11Glu variant was exclusively found in patients without pruritus.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The functional significance of\n                      <jats:italic>MRGPRX4<\/jats:italic>\n                      variants remains unknown. However, some of the variants, including Phe8Leu, Asn25Lys, and Lys11Glu, may alter receptor activity, potentially modulating susceptibility to cholestatic pruritus. Further studies with larger cohorts are warranted to elucidate the mechanistic and clinical relevance of these variants in cholestatic pruritus.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.70587","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T11:27:40Z","timestamp":1773314860000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Defining the Contribution of Genetic Variants in\n                    <scp>\n                      <i>MRGPRX4<\/i>\n                    <\/scp>\n                    With Pruritus in Paediatric Cholestasis: Evidence From Case\u2013Control Study"],"prefix":"10.1111","volume":"46","author":[{"given":"Minna","family":"Rodrigo","sequence":"first","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daphne Chun\u2010Che","family":"Chien","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Kawamoto","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathachit","family":"Limjunyawong","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience Johns Hopkins University School of Medicine  Baltimore Maryland USA"},{"name":"Center of Research Excellence in Allergy and Immunology, Faculty of Medicine Siriraj Hospital Mahidol University  Bangkok Thailand"},{"name":"Department of Immunology, Faculty of Medicine Siriraj Hospital Mahidol University  Bangkok Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songyos","family":"Rajborirug","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Johns Hopkins University Bloomberg School of Public Health  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinzhong","family":"Dong","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7288-5459","authenticated-orcid":false,"given":"Wikrom","family":"Karnsakul","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"issue":"8","key":"e_1_2_13_2_1","first-page":"550","article-title":"The Management of Chronic Pruritus of Cholestasis","volume":"5","author":"Bergasa N.","year":"2009","journal-title":"Gastroenterology & Hepatology"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.5223\/pghn.2016.19.1.1"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2019.04.035"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinre.2018.07.010"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000001958"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-40908-5_10"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2016.06.005"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11901\u2010020\u201000517\u2010x"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25748"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gastro.2005.05.009"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40257\u2010022\u201000710\u20102"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2012.03.010"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000001385"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(21)01256\u20103"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1980"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.14553"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.48431"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1903316116"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010024\u201001794\u20101"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2021.07.078"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adk8198"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3014"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100041\u20101730923"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.104664"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2023.02.002"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.44116"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006045\u20100"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(02)02557-X"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1042\/cs0630065"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002\u20109343(81)90857\u20103"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.10.001"}],"container-title":["Liver International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.70587","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/liv.70587","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.70587","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T05:12:14Z","timestamp":1775884334000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/liv.70587"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,12]]},"references-count":31,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1111\/liv.70587"],"URL":"https:\/\/doi.org\/10.1111\/liv.70587","archive":["Portico"],"relation":{},"ISSN":["1478-3223","1478-3231"],"issn-type":[{"value":"1478-3223","type":"print"},{"value":"1478-3231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,12]]},"assertion":[{"value":"2025-09-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70587"}}