UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking

J Clin Invest. 2022 May 16;132(10):e154997. doi: 10.1172/JCI154997.


Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45AKO Caco-2 cells. In keeping with impaired myosin VB function, UNC45AKO Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45AKO 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease.

Keywords: Epithelial transport of ions and water; Gastroenterology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caco-2 Cells
  • Diarrhea, Infantile* / metabolism
  • Diarrhea, Infantile* / pathology
  • Facies
  • Fetal Growth Retardation
  • Hair Diseases
  • Humans
  • Infant
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Malabsorption Syndromes* / metabolism
  • Microvilli / genetics
  • Microvilli / pathology
  • Mucolipidoses* / genetics
  • Mucolipidoses* / metabolism
  • Mucolipidoses* / pathology
  • Myosin Type V* / genetics
  • Myosin Type V* / metabolism
  • Phenotype
  • Zebrafish / genetics
  • Zebrafish / metabolism


  • Intracellular Signaling Peptides and Proteins
  • UNC45A protein, human
  • Myosin Type V

Supplementary concepts

  • Microvillus inclusion disease
  • Trichohepatoenteric Syndrome