{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T09:49:12Z","timestamp":1781344152661,"version":"3.54.1"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2022,9,3]],"date-time":"2022-09-03T00:00:00Z","timestamp":1662163200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/ http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,2]]},"abstract":"\n Background and Aims:<\/jats:title>\n Porto\u2010sinusoidal vascular disorder (PSVD) is a group of liver vascular diseases featuring lesions encompassing the portal venules and sinusoids unaccompanied by cirrhosis, irrespective of the presence\/absence of portal hypertension. It can occur secondary to coagulation disorders or insult by toxic agents. However, the cause of PSVD remains unknown in most cases. Hereditary cases of PSVD are exceptionally rare, but they are of particular interest and may unveil genetic alterations and molecular mechanisms associated with the disease.<\/jats:p>\n <\/jats:sec>\n \n Approach and Results:<\/jats:title>\n We performed genome sequencing of four patients and two healthy individuals of a large multigenerational Lebanese family with PSVD and identified a heterozygous deleterious variant (c.547C>T, p.R183W) of FCH and double SH3 domains 1 (FCHSD1<\/jats:italic>), an uncharacterized gene, in patients. This variant segregated with the disease, and its pattern of inheritance was suggestive of autosomal dominant with variable expressivity. RNA structural modelling of human FCHSD1<\/jats:italic> suggests that the C\u2010to\u2010T substitution at position 547, corresponding to FCHSD1<\/jats:italic>\n \n R183W\n <\/jats:sup>, may increase both messenger RNA (mRNA) and protein stability and its interaction with MTOR\u2010associated protein, LST8 homolog, a key protein of the mechanistic target of rapamycin (mTOR pathway). These predictions were substantiated by biochemical analyses, which showed that FCHSD1<\/jats:italic>\n \n R183W\n <\/jats:sup> induced high FCHSD1<\/jats:italic> mRNA stability, overexpression of FCHSD1 protein, and an increase in mTORC1 activation. This human FCHSD1<\/jats:italic> variant was introduced into mice through CRISPR\/Cas9 genome editing. Nine out of the 15 mice carrying the human FCHSD1<\/jats:italic>\n \n R183W\n <\/jats:sup> variant mimicked the phenotype of human PSVD, including splenomegaly and enlarged portal vein.<\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n Aberrant FCHSD1 structure and function leads to mTOR pathway overactivation and may cause PSVD.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/hep.32735","type":"journal-article","created":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T02:58:45Z","timestamp":1661137125000},"page":"501-511","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":24,"title":["Genetic predisposition to porto\u2010sinusoidal vascular disorder: A functional genomic\u2010based, multigenerational family study"],"prefix":"10.1097","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0667-6733","authenticated-orcid":false,"given":"Jingxuan","family":"Shan","sequence":"first","affiliation":[{"name":"Genetic Intelligence Laboratory, Weill Cornell Medicine\u2010Qatar, Qatar Foundation, Doha, Qatar"},{"name":"Department of Genetic Medicine, Weill Cornell Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0714-2469","authenticated-orcid":false,"given":"Andr\u00e9","family":"Megarbane","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Gilbert and Rose\u2010Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon"},{"name":"Institut J\u00e9r\u00f4me Lejeune, CRB BioJeL, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aziz","family":"Chouchane","sequence":"additional","affiliation":[{"name":"Faculta di Medicina e Chirurgia, Universita Cattolica del Sacro Cuero, Rome, Italy"},{"name":"Institute of Pathology, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Karthik","sequence":"additional","affiliation":[{"name":"Genetic Intelligence Laboratory, Weill Cornell Medicine\u2010Qatar, Qatar Foundation, Doha, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramzi","family":"Temanni","sequence":"additional","affiliation":[{"name":"Janssen Research and Development, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atilio Reyes","family":"Romero","sequence":"additional","affiliation":[{"name":"Drug Design Group, Department of Pharmacy, University of Groningen, Groningen, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiying","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. 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