Enhanced collagen deposition in the duodenum of patients with hyaline fibromatosis syndrome and protein losing enteropathy

Jorik M. van Rijn, Lael Werner, Yusuf Aydemir, Joey M.A. Spronck, Ben Pode-Shakked, Marliek van Hoesel, Elee Shimshoni, Sylvie Polak-Charcon, Liron Talmi, Makbule Eren, Batia Weiss, Roderick H.J. Houwen, Iris Barshack, Raz Somech, Edward E.S. Nieuwenhuis, Irit Sagi, Annick Raas-Rothschild, Sabine Middendorp*, Dror S. Shouval*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish
Article number8200
Pages (from-to)1-16
Number of pages16
JournalInternational Journal of Molecular Sciences
Issue number21
StatePublished - 1 Nov 2020


FundersFunder number
Leona M. and Harry B. Helmsley Charitable Trust
Nederlandse Organisatie voor Wetenschappelijk Onderzoek


    • ANTXR2
    • CMG2
    • Extracellular matrix
    • Intestinal lymphangiectasia
    • Organoids
    • Protein losing enteropathy


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