ArticleThe Journal of clinical investigation2022
UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 29 citations in OpenAlex.
- Microvillus inclusion disease-associated MYO5B deficiency impairs endosome-to-mitochondrion iron transfer.Gastroenterology report · 2026Article
- MYO1B in human disease: an actin-based motor linking membrane trafficking to oncogenic signaling, metastasis, and vascular aging.Frontiers in oncology · 2026Review
- Primary human intestinal organoids with biallelic UNC45A variants suggest role of cystic fibrosis transmembrane conductance regulator in pathogenesis of UNC45A-related intestinal disorder.Journal of pediatric gastroenterology and nutrition · 2026Article
- A Case Report and Literature Review on Osteo-Oto-Hepato-Enteric Syndrome in Premature Infants Caused by UNC45A Deficiency.Molecular genetics & genomic medicine · 2025Review
- Advances in Understanding Intestinal Homeostasis: Lessons from Inflammatory Bowel Disease and Monogenic Intestinal Disorder Pathogenesis.International journal of molecular sciences · 2025Review
- Alazami syndrome with a single LARP7 variant and concurrent osteo-oto-hepato-enteric syndrome: A case of complex genetic interplay.Radiology case reports · 2025Article
- Paediatric Congenital Enteropathies: Clinical and Histological Review.Diagnostics (Basel, Switzerland) · 2025Review
- Altered chaperone-nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T>C variant in osteo-oto-hepato-enteric syndrome.JCI insight · 2025Article
- Myosin Vb Traffics P-Glycoprotein to the Apical Membrane of Intestinal Epithelial Cells.Gastroenterology · 2025Article
- Newly Described Mutations of theCurrent pediatric reviews · 2025Article
- An update on autophagy disorders.Journal of inherited metabolic disease · 2025Review
- Microvillous Inclusion Disease: An Exceedingly Rare Condition With a New Treatment.ACG case reports journal · 2024Article
- Cellular and molecular basis of proximal small intestine disorders.Nature reviews. Gastroenterology & hepatology · 2024Review
- Modeling the cell biology of monogenetic intestinal epithelial disorders.The Journal of cell biology · 2024Review
- Review
- Downregulation of V-ATPase VCellular and molecular gastroenterology and hepatology · 2024Article
- The genetics of monogenic intestinal epithelial disorders.Human genetics · 2023Review
- A CRISPR screen in intestinal epithelial cells identifies novel factors for polarity and apical transport.eLife · 2023Article
- Case report: Osteo-oto-hepato-enteric syndrome caused by UNC45A deficiency.Frontiers in genetics · 2022Article
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Authors and funding
37 authors at 9 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
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 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.
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