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
N1 - Funding Information:
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 .
Publisher Copyright:
© 2018 American Society of Human Genetics
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
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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U2 - 10.1016/j.ajhg.2018.01.009
DO - 10.1016/j.ajhg.2018.01.009
M3 - Article
C2 - 29429573
AN - SCOPUS:85042540848
VL - 102
SP - 364
EP - 374
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -
