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

Clothilde Esteve, Ludmila Francescatto, Perciliz L. Tan, Aurélie Bourchany, Cécile De Leusse, Evelyne Marinier, Arnaud Blanchard, Patrice Bourgeois, Céline Brochier-Armanet, Ange Line Bruel, Arnauld Delarue, Yannis Duffourd, Emmanuelle Ecochard-Dugelay, Géraldine Hery, Frédéric Huet, Philippe Gauchez, Emmanuel Gonzales, Catherine Guettier-Bouttier, Mina Komuta, Caroline LacosteRaphaelle Maudinas, Karin Mazodier, Yves Rimet, Jean Baptiste Rivière, Bertrand Roquelaure, Sabine Sigaudy, Xavier Stephenne, Christel Thauvin-Robinet, Julien Thevenon, Jacques Sarles, Nicolas Levy, Catherine Badens, Olivier Goulet, Jean Pierre Hugot, Elias Nicholas Katsanis, Laurence Faivre, Alexandre Fabre*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)364-374
Number of pages11
JournalAmerican journal of human genetics
Volume102
Issue number3
DOIs
StatePublished - Mar 1 2018

Keywords

  • GCUNC-45

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    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., ... Fabre, A. (2018). Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility. American journal of human genetics, 102(3), 364-374. https://doi.org/10.1016/j.ajhg.2018.01.009