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

January 09, 2018

Authors: Clothilde Esteve, Ludmila Francescatto, Perciliz L. Tan, Aurélie Bourchany, Ccile 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 Lacoste, Raphaelle 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, Nicholas Katsanis, Laurence Faivrem and Alexandre Fabre.

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. In conclusion, our study finds a strong association between UNC45A loss-of-function mutations and a syndrome, we named osteo-oto-hepato-enteric (O2HE) syndrome. According to previous reports, UNC45A is possibly associated with the cytoskeleton and further evidence needs to be accumulated to understand the molecular mechanisms underlying the O2HE syndrome.

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