Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy
| Autor: | Marliek van Hoesel, Jorik M. van Rijn, Batia Weiss, Makbule Eren, Iris Barshack, Roderick H. J. Houwen, Dror S. Shouval, Joey M A Spronck, Liron Talmi, Annick Raas-Rothschild, Raz Somech, Sabine Middendorp, Edward E. S. Nieuwenhuis, Elee Shimshoni, Sylvie Polak-Charcon, Ben Pode-Shakked, Irit Sagi, Yusuf Aydemir, Lael Werner |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Pathology Cell- och molekylärbiologi medicine.disease_cause CMG2 lcsh:Chemistry Extracellular matrix Consanguinity Hyalinosis Systemic 0302 clinical medicine Collagen VI Enteropathy lcsh:QH301-705.5 Spectroscopy organoids Mutation Chemistry Protein losing enteropathy General Medicine ANTXR2 Computer Science Applications Phenotype medicine.anatomical_structure 030211 gastroenterology & hepatology Collagen Signal Transduction Diarrhea medicine.medical_specialty Receptors Peptide Duodenum protein losing enteropathy Protein-Losing Enteropathies extracellular matrix Bacterial Toxins Article Catalysis Inorganic Chemistry 03 medical and health sciences intestinal lymphangiectasia Organoid medicine Humans Physical and Theoretical Chemistry Molecular Biology Antigens Bacterial Organic Chemistry Infant medicine.disease Epithelium Microscopy Electron 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 CRISPR-Cas Systems Cell and Molecular Biology |
| Zdroj: | International Journal of Molecular Sciences Volume 21 Issue 21 International Journal of Molecular Sciences, Vol 21, Iss 8200, p 8200 (2020) |
| Popis: | 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> 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. |
| Databáze: | OpenAIRE |
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