ZFIN ID: ZDB-PUB-181212-31
Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility
Esteve, C., Francescatto, L., Tan, P.L., Bourchany, A., De Leusse, C., Marinier, E., Blanchard, A., Bourgeois, P., Brochier-Armanet, C., Bruel, A.L., Delarue, A., Duffourd, Y., Ecochard-Dugelay, E., Hery, G., Huet, F., Gauchez, P., Gonzales, E., Guettier-Bouttier, C., Komuta, M., Lacoste, C., Maudinas, R., Mazodier, K., Rimet, Y., Rivière, J.B., Roquelaure, B., Sigaudy, S., Stephenne, X., Thauvin-Robinet, C., Thevenon, J., Sarles, J., Levy, N., Badens, C., Goulet, O., Hugot, J.P., Katsanis, N., Faivre, L., Fabre, A.
Date: 2018
Source: American journal of human genetics   102: 364-374 (Journal)
Registered Authors: Francescatto, Ludmila, Katsanis, Nicholas
Keywords: GCUNC-45
MeSH Terms:
  • Adolescent
  • Animals
  • Bone and Bones/pathology*
  • Child, Preschool
  • Cholestasis/genetics*
  • Diarrhea/genetics*
  • Diarrhea/physiopathology
  • Family
  • Female
  • Fibroblasts/pathology
  • Gastrointestinal Motility
  • Hearing Loss/genetics*
  • Humans
  • Infant, Newborn
  • Intracellular Signaling Peptides and Proteins/genetics*
  • Loss of Function Mutation/genetics*
  • Lymphocytes/pathology
  • Male
  • Pedigree
  • Phenotype
  • Syndrome
  • Young Adult
  • Zebrafish
PubMed: 29429573 Full text @ Am. J. Hum. Genet.
Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.