{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T12:35:02Z","timestamp":1775910902240,"version":"3.50.1"},"reference-count":43,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,11,2]],"date-time":"2020-11-02T00:00:00Z","timestamp":1604275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Netherlands Organisation for Scientific Research (NWO-ZonMW-VIDI)","award":["016.146.353"],"award-info":[{"award-number":["016.146.353"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hyaline fibromatosis syndrome (HFS), resulting from ANTXR2 mutations, is an ultra-rare disease that causes intestinal lymphangiectasia and protein-losing enteropathy (PLE). The mechanisms leading to the gastrointestinal phenotype in these patients are not well defined. We present two patients with congenital diarrhea, severe PLE and unique clinical features resulting from deleterious ANTXR2 mutations. Intestinal organoids were generated from one of the patients, along with CRISPR-Cas9 ANTXR2 knockout, and compared with organoids from two healthy controls. The ANTXR2-deficient organoids displayed normal growth and polarity, compared to controls. Using an anthrax-toxin assay we showed that the c.155C&gt;T mutation causes loss-of-function of ANTXR2 protein. An intrinsic defect of monolayer formation in patient-derived or ANTXR2KO organoids was not apparent, suggesting normal epithelial function. However, electron microscopy and second harmonic generation imaging showed abnormal collagen deposition in duodenal samples of these patients. Specifically, collagen VI, which is known to bind ANTXR2, was highly expressed in the duodenum of these patients. In conclusion, despite resistance to anthrax-toxin, epithelial cell function, and specifically monolayer formation, is intact in patients with HFS. Nevertheless, loss of ANTXR2-mediated signaling leads to collagen VI accumulation in the duodenum and abnormal extracellular matrix composition, which likely plays a role in development of PLE.<\/jats:p>","DOI":"10.3390\/ijms21218200","type":"journal-article","created":{"date-parts":[[2020,11,2]],"date-time":"2020-11-02T09:04:46Z","timestamp":1604307886000},"page":"8200","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2865-4455","authenticated-orcid":false,"given":"Jorik M.","family":"van Rijn","sequence":"first","affiliation":[{"name":"Division of Pediatrics, Department of Pediatric Gastroenterology, Wilhelmina Children\u2019s Hospital, University Medical Center Utrecht (UMCU), Utrecht University (UU), 3584 CT Utrecht, The Netherlands"},{"name":"Regenerative Medicine Center, UMCU, UU, 3584 CT Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3590-2798","authenticated-orcid":false,"given":"Lael","family":"Werner","sequence":"additional","affiliation":[{"name":"Pediatric Gastroenterology Unit, Edmond and Lily Safra Children\u2019s Hospital, Sheba Medical Center, Ramat Gan 5262100, Israel"},{"name":"Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3318-2747","authenticated-orcid":false,"given":"Yusuf","family":"Aydemir","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, Eskisehir Osmangazi University Faculty of Medicine, Eskisehir 26040, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9653-9542","authenticated-orcid":false,"given":"Joey M.A.","family":"Spronck","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Pediatric Gastroenterology, Wilhelmina Children\u2019s Hospital, University Medical Center Utrecht (UMCU), Utrecht University (UU), 3584 CT Utrecht, The Netherlands"},{"name":"Regenerative Medicine Center, UMCU, UU, 3584 CT Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ben","family":"Pode-Shakked","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel"},{"name":"The Institute for Rare Diseases, Edmond and Lily Safra Children\u2019s Hospital, Sheba Medical Center, Ramat Gan 5262100, Israel"},{"name":"Talpiot Medical Leadership Program, Sheba Medical Center, Ramat Gan 5262100, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marliek","family":"van Hoesel","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Pediatric Gastroenterology, Wilhelmina Children\u2019s Hospital, University Medical Center Utrecht (UMCU), Utrecht University (UU), 3584 CT Utrecht, The Netherlands"},{"name":"Regenerative Medicine Center, UMCU, UU, 3584 CT Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elee","family":"Shimshoni","sequence":"additional","affiliation":[{"name":"Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvie","family":"Polak-Charcon","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel"},{"name":"Institute of Pathology, Sheba Medical Center, Ramat Gan 5262100, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liron","family":"Talmi","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel"},{"name":"Pediatric Department A, Edmond and Lily Safra Children\u2019s Hospital, Sheba Medical Center, Ramat Gan 5262100, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7105-7165","authenticated-orcid":false,"given":"Makbule","family":"Eren","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, Eskisehir Osmangazi University Faculty of Medicine, Eskisehir 26040, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Batia","family":"Weiss","sequence":"additional","affiliation":[{"name":"Pediatric Gastroenterology Unit, Edmond and Lily Safra Children\u2019s Hospital, Sheba Medical Center, Ramat Gan 5262100, 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Houwen","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Pediatric Gastroenterology, Wilhelmina Children\u2019s Hospital, University Medical Center Utrecht (UMCU), Utrecht University (UU), 3584 CT Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iris","family":"Barshack","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel"},{"name":"Institute of Pathology, Sheba Medical Center, Ramat Gan 5262100, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raz","family":"Somech","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel"},{"name":"Pediatric Department A, Edmond and Lily Safra Children\u2019s Hospital, Sheba Medical Center, Ramat Gan 5262100, Israel"},{"name":"Immunology Service, Edmond and Lily Safra Children\u2019s Hospital, Sheba Medical Center, Ramat Gan 5262100, Israel"},{"name":"Jeffrey Modell Foundation Center, Edmond and Lily Safra Children\u2019s Hospital, Sheba Medical Center, Ramat Gan 5262100, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward E.S.","family":"Nieuwenhuis","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Pediatric Gastroenterology, Wilhelmina Children\u2019s Hospital, University Medical Center Utrecht (UMCU), Utrecht University (UU), 3584 CT Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irit","family":"Sagi","sequence":"additional","affiliation":[{"name":"Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annick","family":"Raas-Rothschild","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel"},{"name":"The Institute for Rare Diseases, Edmond and Lily Safra Children\u2019s Hospital, Sheba Medical Center, Ramat Gan 5262100, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0925-0095","authenticated-orcid":false,"given":"Sabine","family":"Middendorp","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Pediatric Gastroenterology, Wilhelmina Children\u2019s Hospital, University Medical Center Utrecht (UMCU), Utrecht University (UU), 3584 CT Utrecht, The Netherlands"},{"name":"Regenerative Medicine Center, UMCU, UU, 3584 CT Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dror S.","family":"Shouval","sequence":"additional","affiliation":[{"name":"Pediatric Gastroenterology Unit, Edmond and Lily Safra Children\u2019s Hospital, Sheba Medical Center, Ramat Gan 5262100, Israel"},{"name":"Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15861","DOI":"10.1038\/ncomms15861","article-title":"CMG2\/ANTXR2 regulates extracellular collagen VI which accumulates in hyaline fibromatosis syndrome","volume":"8","author":"Burgi","year":"2017","journal-title":"Nat. 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