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Identification of intestinal ion transport defects in microvillus inclusion disease

Dmitri V Kravtsov1, Md Kaimul Ahsan1, Vandana Kumari1

  • 1Department of Pediatrics/Gastroenterology and Hepatology, Yale School of Medicine, New Haven, Connecticut;

American Journal of Physiology. Gastrointestinal and Liver Physiology
|May 28, 2016
PubMed

Insights

Loss of myosin Vb (Myo5b) impairs enterocyte maturation, reducing sodium and chloride absorption. This leads to microvillus inclusion disease (MVID) diarrhea due to defects in key ion transporters.

Area of Science:

  • Gastroenterology
  • Cell Biology
  • Molecular Medicine

Background:

  • Loss-of-function mutations in myosin Vb (Myo5b) cause microvillus inclusion disease (MVID), a fatal condition in newborns and children.
  • MVID is characterized by secretory diarrhea, brush border defects, villus atrophy, and microvillus inclusions in enterocytes.
  • The mechanism by which Myo5b loss leads to excessive chloride and sodium loss in stool remains unclear.

Purpose of the Study:

  • To investigate the role of Myo5b in enterocyte maturation and its impact on intestinal ion transport.
  • To examine the distribution, expression, and function of major brush border ion transporters (NHE3, CFTR, DRA) in the absence of Myo5b.
  • To elucidate the molecular mechanisms underlying diarrhea in MVID.

Main Methods:

  • Utilized human MVID intestine and polarized intestinal cell models (T84, C2BBe) with Myo5b knockdown.
  • Employed immunofluorescence confocal stimulated emission depletion (gSTED) imaging, immunohistochemistry, transmission electron microscopy, shRNA silencing, immunoblots, and electrophysiology.
  • Assessed the localization and function of NHE3, CFTR, and DRA in Myo5b-deficient enterocytes.

Main Results:

  • Myosin Vb deficiency resulted in reduced brush border localization and function of NHE3 and DRA, while CFTR localization remained intact.
  • Forskolin-stimulated CFTR ion transport was preserved in Myo5b-deficient secretory T84 cells.
  • Loss of Myo5b caused YAP1 nuclear retention, delayed enterocyte maturation, and induced a cryptlike phenotype.

Conclusions:

  • Preserved CFTR function in immature enterocytes, coupled with reduced functional expression of NHE3 and DRA, contributes to chloride and sodium loss in MVID diarrhea.
  • Myo5b is crucial for enterocyte maturation and proper brush border organization of ion transporters.
  • Defective enterocyte maturation and ion transport are key pathogenic mechanisms in MVID.
Keywords:
CFTRMVIMVIDMyo5bNHE3brush border

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