UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking - Archive ouverte HAL Access content directly
Journal Articles Journal of Clinical Investigation Year : 2022

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

(1, 2) , (1) , (3) , (1, 2) , (4) , (5, 6) , (7) , (7) , (1) , (2) , (8, 9) , (10) , (11, 12) , (13) , (7) , (10) , (1) , (1) , (10, 1) , (2) , (2) , (14) , (15) , (7) , (2) , (16) , (16) , (7) , (7) , (7) , (17) , (2) , (16) , (6, 5) , (4, 18, 19) , (1) , (1)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Taras Valovka
  • Function : Author
  • PersonId : 892100
Marion Rabant
  • Function : Author
  • PersonId : 1072355
Cecile Talbotec
  • Function : Author
  • PersonId : 912477
Thomas Mueller

Abstract

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 UNC45A(KO) Caco-2 cells. In keeping with impaired myosin VB function, UNC45A(KO) Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45A(KO) 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.
Fichier principal
Vignette du fichier
pdf (5.8 Mo) Télécharger le fichier
Origin : Publisher files allowed on an open archive

Dates and versions

hal-03756921 , version 1 (22-08-2022)

Licence

Attribution - CC BY 4.0

Identifiers

Cite

Rémi Duclaux-Loras, Corinne Lebreton, Jérémy Berthelet, Fabienne Charbit-Henrion, Ophélie Nicolle, et al.. UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking. Journal of Clinical Investigation, 2022, 132 (10), ⟨10.1172/JCI154997⟩. ⟨hal-03756921⟩
34 View
1 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More