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 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; Elias Nicholas Katsanis; Laurence Faivre; Alexandre Fabre

doi:10.1016/j.ajhg.2018.01.009

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

Pediatrics

Research output: Contribution to journal › Article › peer-review

34 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 language	English (US)
Pages (from-to)	364-374
Number of pages	11
Journal	American journal of human genetics
Volume	102
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2018.01.009
State	Published - Mar 1 2018

Funding

We are grateful to all the affected individuals and their families who participated in this study. We would like to thank Beth Roman for sharing the kurzschlusstr12 zebrafish, Jennifer Bagwell and Michel Bagnat for their expert advice on intestinal phenotyping and antibodies, and Melanie Garrett and Allison Ashley-Koch for their assistance with the statistical analysis of the zebrafish work. We also thank Erica Davis and Michael Mitchell for critical reading of the manuscript and helpful suggestions and Nathalie Colavolpe for her help with X-ray. This work was supported in part by grants from the Fondation Maladies Rares ( WES20150601 ), AMGORE (Association Méditerranéenne pour les Greffes d’ORganes aux Enfants) , the Regional Council of Burgundy ( PARI 2014 ), the GFHGNP (Groupe Francophone d’Hépatologie-Gastroentérologie et Nutrition Pédiatriques, “Prix de recherche du Groupe Francophone d'Hépatologie, Gastro-entérologie et de Nutrition Pédiatriques 2015”) , and the patient support group Association Romy - La vie par un fil .

Keywords

GCUNC-45

ASJC Scopus subject areas

Genetics
Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ajhg.2018.01.009

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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

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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.",

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Esteve, C, Francescatto, L, Tan, PL, Bourchany, A, De Leusse, C, Marinier, E, Blanchard, A, Bourgeois, P, Brochier-Armanet, C, Bruel, AL, 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, JB, Roquelaure, B, Sigaudy, S, Stephenne, X, Thauvin-Robinet, C, Thevenon, J, Sarles, J, Levy, N, Badens, C, Goulet, O, Hugot, JP, Katsanis, EN, Faivre, L & 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, vol. 102, no. 3, pp. 364-374. https://doi.org/10.1016/j.ajhg.2018.01.009

TY - JOUR

T1 - Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility

AU - Esteve, Clothilde

AU - Francescatto, Ludmila

AU - Tan, Perciliz L.

AU - Bourchany, Aurélie

AU - De Leusse, Cécile

AU - Marinier, Evelyne

AU - Blanchard, Arnaud

AU - Bourgeois, Patrice

AU - Brochier-Armanet, Céline

AU - Bruel, Ange Line

AU - Delarue, Arnauld

AU - Duffourd, Yannis

AU - Ecochard-Dugelay, Emmanuelle

AU - Hery, Géraldine

AU - Huet, Frédéric

AU - Gauchez, Philippe

AU - Gonzales, Emmanuel

AU - Guettier-Bouttier, Catherine

AU - Komuta, Mina

AU - Lacoste, Caroline

AU - Maudinas, Raphaelle

AU - Mazodier, Karin

AU - Rimet, Yves

AU - Rivière, Jean Baptiste

AU - Roquelaure, Bertrand

AU - Sigaudy, Sabine

AU - Stephenne, Xavier

AU - Thauvin-Robinet, Christel

AU - Thevenon, Julien

AU - Sarles, Jacques

AU - Levy, Nicolas

AU - Badens, Catherine

AU - Goulet, Olivier

AU - Hugot, Jean Pierre

AU - Katsanis, Elias Nicholas

AU - Faivre, Laurence

AU - Fabre, Alexandre

PY - 2018/3/1

Y1 - 2018/3/1

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AB - 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.

KW - GCUNC-45

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DO - 10.1016/j.ajhg.2018.01.009

M3 - Article

C2 - 29429573

AN - SCOPUS:85042540848

SN - 0002-9297

VL - 102

SP - 364

EP - 374

JO - American journal of human genetics

JF - American journal of human genetics

IS - 3

ER -

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

Abstract

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Keywords

ASJC Scopus subject areas

UN SDGs

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