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. 2025;19(8):101514.
doi: 10.1016/j.jcmgh.2025.101514. Epub 2025 Apr 11.

Loss of WNT2B Results in Epithelial Defects and Predisposes to Gastrointestinal Dysplasia in Humans

Leslie Lori  1 , Valentin Neuranter  1 , Corinne Lebreton  1 , Jérémy Berthelet  2 , Marianna Parlato  1 , Christina Michail  2 , Anis Khiat  1 , Dominique Berrebi  3 , Julie Bruneau  3 , Benoit Terris  4 , Georgia Malamut  5 , Sylvain Hanein  6 , Yohann Schmitt  7 , Céline Banal  8 , Fernando Rodrigues Lima  9 , Emilie Azouguene  10 , Frank Ruemmele  11 , Cecile Talbotec  12 , Cecile Lambe  11 , Nadine Cerf-Bensussan  1 , Fabienne Charbit-Henrion  13
Affiliations

Loss of WNT2B Results in Epithelial Defects and Predisposes to Gastrointestinal Dysplasia in Humans

Leslie Lori et al. Cell Mol Gastroenterol Hepatol. 2025.
No abstract available

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Figures

Figure 1
Figure 1
WNT2B variants in P1 and P2 are loss of function and result in stem cell defect. (A) Familial segregation of WNT2B variants. (B) Schematic representation of WNT2B protein; Inter-species conservation of Leu265 among orthologs. (C) Sequencing of cDNA synthetized from mRNA extracted from P2’s duodenal biopsy showing an 18-bp intronic sequence retention, resulting in a 6-amino acid insertion (VSTHVC). (D) Expression of Leu265Pro and Thr227ins variants in HEK293T cells transfected with pLenti-C encoding myc-WT-WNT2B, myc-Leu265Pro-WNT2B and myc-Thr227+6-WNT2B revealed by anti-myc antibody. GAPDH = loading control. pPURO-FLAG-HA-EGFP plasmid = transfection control. (E) Left: Stabilizing and destabilizing effects of the Leu265Pro-WNT2B variant, as well as the position of the α-helix bundles (137-159, 213-232, 259-270) are displayed. Right: Global structure of the Leu265Pro-WNT2B mutant. Regions with positive differences in vibrational entropy compared with WNT2B-WT are in red (level of red increases with the intensity of the difference). Inset: Close-up view of an interaction discrepancy caused by the Leu265Pro variant. WT and Leu265Pro are in gray and red, respectively. Van der Waals radii are shown for each side chain atom. (F) Left: Dimplots of the interactions between the α-helix bundle residues in the WT (far left) and Thr227ins mutant (center) (numbering of the WT-WNT2B residues in gray). Hydrophobic interactions are shown as red cilia and hydrogen bonds as green dashed lines. Right: Structural alignment of WT (gray) and Thr227ins (blue) WNT2B proteins. 213-232 and 258-270 α-helices, where the disappearance of the hydrogen bond between residues R231 and Y264, are shown in green. Numbering of the Thr227ins WNT2B mutant residues is displayed in blue. (G) OLFM4, LGR5 and AXIN2 mRNA expression by qRT-PCR in P1’s antral biopsy. (H) Patients’ antral biopsies, H&E staining, magnification 100×.
Figure 2
Figure 2
WNT2B loss gives rise to an abnormal intestinal epithelial phenotype and predisposes to the emergence of somatic variants. (A) DRA, NHE3, DPPIV, SI, and phospho-Ezrin expression in patients‘ duodenal biopsies by immunofluorescence (P1, age 9; P2, age 4 months old). DAPI: nuclei staining (blue); Scale bar = 10 μm. (B) Abnormal antral metaplasia in P1’s duodenal biopsy in H&E and PAS staining. (C) P1’s duodenal biopsy showing strong abnormal expression of gatric mucin MUC5AC. DAPI: nuclei staining, blue; Scale bar: 10 μm; confocal microcoscopy. (D) : Abnormal mRNA expression of MUC5AC in 2 distincts duodenal biopsies in P1, compared with P2 and healthy control. (E) H&E staining of antral adenoma with intestinal metaplasia and high-grade dysplasia with high-grade dysplasia, resected at age 10, low and high magnification. (F) Immunohistochemical staining of β-catenin, Ki67, and TP53 in same antral adenoma. (G) Main somatic variants identified by paired somatic-germline exome analysis. (H) OLFM4, LGR5, and AXIN2 mRNA expression by RT-qPCR in non-dysplastic antrum of P1 compared with her precancerous lesion.
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