@article {1319475,
	title = {Neonatal-Onset Chronic Diarrhea Caused by Homozygous Nonsense WNT2B Mutations},
	journal = {Am J Hum Genet},
	volume = {103},
	number = {1},
	year = {2018},
	month = {2018 Jul 05},
	pages = {131-137},
	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\&nbsp;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\&nbsp;explaining their diarrheal phenotype. WNT2B deficiency should be considered for individuals with neonatal-onset diarrhea.},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2018.05.007},
	author = {O{\textquoteright}Connell, Amy E and Zhou, Fanny and Shah, Manasvi S and Murphy, Quinn and Rickner, Hannah and Kelsen, Judith and Boyle, John and Doyle, Jefferson J and Gangwani, Bharti and Thiagarajah, Jay R and Kamin, Daniel S and Goldsmith, Jeffrey D and Richmond, Camilla and Breault, David T and Agrawal, Pankaj B}
}
