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

Clothilde Esteve (1) , Ludmila Francescatto , Perciliz Tan , Aurélie Bourchany (2) , Cécile de Leusse , Evelyne Marinier (3) , Arnaud Blanchard (1) , Patrice Bourgeois (1, 4) , Céline Brochier-Armanet (5) , Ange-Line Bruel (6) , Arnauld Delarue (7) , Yannis Duffourd (6) , Emmanuel Ecochard-Dugelay , Géraldine Héry (8, 9) , Frédéric Huet (10) , Philippe Gauchez , Emmanuel Gonzales (11) , Catherine Guettier-Bouttier , Mina Komuta , Caroline Lacoste (1, 12) , Raphaelle Maudinas , Karin Mazodier , Yves Rimet , Jean-Baptiste Riviere (6) , Bertrand Roquelaure (13) , Sabine Sigaudy (14, 1) , Xavier Stephenne , Christel Thauvin-Robinet (15) , Julien Thevenon (10) , Jacques Sarles (16) , Nicolas Lévy (14, 1) , Catherine Badens (17, 1, 14) , Olivier Goulet (18) , Jean-Pierre Hugot (19) , Nicholas Katsanis (20) , Laurence Faivre (6) , Alexandre Fabre (1, 8)

1 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
2 Equipe GAD (LNC - U1231)
3 Department of Pediatric Gastroenterology
4 Neuro-Oncologie [Hôpital de la Timone - APHM]
5 BPGE - Bioinformatique, phylogénie et génomique évolutive
6 GAD - Génétique des Anomalies du Développement
7 TIMONE - Hôpital de la Timone [CHU - APHM]
8 Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM]
9 CERIMED - Centre Européen de Recherche en Imagerie médicale
10 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
11 Signalisation calcique et interactions cellulaires dans le foie
12 Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM]
13 Service de pédiatrie multidiciplinaire
14 Département de génétique médicale [Hôpital de la Timone - APHM]
15 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
16 Service de Pédiatrie Multidisciplinaire
17 Centre de référence maladie rare Thalassémie
18 CHU Necker - Enfants Malades [AP-HP]
19 OSEB - Origine, structure et évolution de la biodiversité
20 Center for Human Disease Modeling

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.

Keywords: GCUNC-45

Domains: Life Sciences [q-bio]; Genetics; Human genetics

Clothilde Esteve, Ludmila Francescatto, Perciliz Tan, Aurélie Bourchany, Cécile de Leusse, et al.. Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility. American Journal of Human Genetics, 2018, 102 (3), pp.364 - 374. ⟨10.1016/j.ajhg.2018.01.009⟩. ⟨hal-01721495⟩