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

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

doi:10.1016/j.ajhg.2018.01.009

Journal articles

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)

LNC - Lipides - Nutrition - Cancer [Dijon - U1231]

3 Department of Pediatric Gastroenterology

4 Neuro-Oncologie [Hôpital de la Timone - APHM]

5 BPGE - Bioinformatique, phylogénie et génomique évolutive

PEGASE - Département PEGASE [LBBE]

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]

Département de génétique médicale [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

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.

Keywords : GCUNC-45

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Genetics / Human genetics

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https://hal-amu.archives-ouvertes.fr/hal-01721495
Contributor : Clothilde Esteve Connect in order to contact the contributor
Submitted on : Friday, March 2, 2018 - 11:08:23 AM
Last modification on : Wednesday, January 19, 2022 - 2:04:02 PM

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

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

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