Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility.


Journal Article

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.

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Cited Authors

  • Esteve, C; Francescatto, L; Tan, PL; 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

Published Date

  • March 1, 2018

Published In

Volume / Issue

  • 102 / 3

Start / End Page

  • 364 - 374

PubMed ID

  • 29429573

Pubmed Central ID

  • 29429573

Electronic International Standard Serial Number (EISSN)

  • 1537-6605

Digital Object Identifier (DOI)

  • 10.1016/j.ajhg.2018.01.009


  • eng

Conference Location

  • United States