Neonatal-Onset Chronic Diarrhea Caused by Homozygous Nonsense WNT2B Mutations

Amy E. O'Connell, Fanny Zhou, Manasvi S. Shah, Quinn Murphy, Hannah Rickner, Judith Kelsen, John Boyle, Jefferson Doyle, Bharti Gangwani, Jay R. Thiagarajah, Daniel S. Kamin, Jeffrey D. Goldsmith, Camilla Richmond, David T. Breault, Pankaj B. Agrawal

Research output: Contribution to journalArticle

Abstract

Homozygous nonsense mutations in WNT2B were identified in three individuals from two unrelated families with severe, neonatal-onset osmotic diarrhea after whole-exome sequencing was performed on trios from the two families. Intestinal biopsy samples from affected individuals were used for histology and immunofluorescence and to generate enteroids ex vivo. Histopathologic evaluation demonstrated chronic inflammatory changes in the stomach, duodenum, and colon. Immunofluorescence demonstrated diminished staining for OLFM4, a marker for intestinal stem cells (ISCs). The enteroids generated from WNT2B-deficient intestinal epithelium could not be expanded and did not survive passage. Addition of CHIR-99021 (a GSK3A and GSK3B inhibitor and activator of canonical WNT/β-CATENIN signaling) could not rescue WNT2B-deficient enteroids. Addition of supplemental recombinant murine WNT2B was able to perpetuate small enteroids for multiple passages but failed to expand their number. Enteroids showed a 10-fold increase in the expression of LEF1 mRNA and a 100-fold reduction in TLR4 expression, compared with controls by quantitative RT-PCR, indicating alterations in canonical WNT and microbial pattern-recognition signaling. In summary, individuals with homozygous nonsense mutations in WNT2B demonstrate severe intestinal dysregulation associated with decreased ISC number and function, likely explaining their diarrheal phenotype. WNT2B deficiency should be considered for individuals with neonatal-onset diarrhea.

Original languageEnglish (US)
Pages (from-to)131-137
Number of pages7
JournalAmerican Journal of Human Genetics
Volume103
Issue number1
DOIs
Publication statusPublished - Jul 5 2018
Externally publishedYes

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Keywords

  • CODE
  • congenital diarrhea and enteropathy
  • diarrhea
  • intestinal stem cells
  • Lgr5
  • OLFM4
  • TLR4
  • WNT2B

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

O'Connell, A. E., Zhou, F., Shah, M. S., Murphy, Q., Rickner, H., Kelsen, J., ... Agrawal, P. B. (2018). Neonatal-Onset Chronic Diarrhea Caused by Homozygous Nonsense WNT2B Mutations. American Journal of Human Genetics, 103(1), 131-137. https://doi.org/10.1016/j.ajhg.2018.05.007