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Am J Hum Genet. 2018 Mar 1;102(3):364-374. doi: 10.1016/j.ajhg.2018.01.009. Epub 2018 Feb 8.

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

Author information

1
Aix Marseille Univ, INSERM, MMG, 13385 Marseille, France.
2
Center for Human Disease Modeling, Duke University, Durham, NC, USA.
3
Center for Human Disease Modeling, Duke University, Durham, NC, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27701, USA.
4
Equipe GAD, UMR1231 Inserm, Université de Bourgogne Franche Comté, 21079 Dijon, France; Service de Pédiatrie, Hôpital D'Enfants, CHU, 21000 Dijon, France.
5
Service de pédiatrie multidisciplinaire, Hôpital de la Timone Enfants, APHM, 13385 Marseille, France.
6
Service des maladies digestives et respiratoires de l'enfant, Hôpital Robert Debré, APHP, 75019 Paris, France.
7
Aix Marseille Univ, INSERM, MMG, 13385 Marseille, France; Service de biologie moléculaire, Hôpital de la Timone Enfants, APHM, 13385 Marseille, France.
8
Univ Lyon, Université Claude Bernard Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Évolutive (UMR CNRS / Lyon 1 5558), 69622 Villeurbanne, France.
9
Equipe GAD, UMR1231 Inserm, Université de Bourgogne Franche Comté, 21079 Dijon, France.
10
Equipe GAD, UMR1231 Inserm, Université de Bourgogne Franche Comté, 21079 Dijon, France; Centre de Référence Anomalies du Développement et Syndromes Malformatifs et FHU TRANSLAD, CHU, 21000 Dijon, France.
11
Service de Pédiatrie, Hôpital D'Enfants, CHU, 21000 Dijon, France.
12
Pediatric hepatology and pediatric liver transplantation unit and National Reference Centre for rare pediatric liver diseases, Hepatinov, Bicêtre Universitary Hospital, University of Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, 94800 Villejuif, France; Inserm, UMR-S1174, Hepatinov, University of Paris-Sud 11, 91405 Orsay, France.
13
Pathology Unit, Bicêtre Universitary Hospital, University of Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, 94800 Villejuif, France.
14
Anatomopathology Department, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium.
15
Service de biologie moléculaire, Hôpital de la Timone Enfants, APHM, 13385 Marseille, France.
16
Internal medicine and clinical, Hôpital Conception, APHM, 13005 Marseille, France.
17
Service de Pédiatrie-Néonatologie, Centre Hospitalier Intercommunal Aix-Pertuis, 13616 Aix en Provence, France.
18
Département de Génétique Médicale, Hôpital de la Timone Enfants de La Timone, APHM, 13385 Marseille, France.
19
Université catholique de Louvain, Cliniques universitaires St Luc, Département de pédiatrie, Service de gastroentérologie et hépatologie pédiatrique, 1200 Bruxelles, Belgique.
20
Department of Pediatric Gastroenterology, Hepatology and Nutrition, Reference center for Rare Digestive Diseases; Hôpital Necker; University Paris-Cité-Sorbonne; Paris-Descartes Medical School, 75006 Paris, France.
21
Aix Marseille Univ, INSERM, MMG, 13385 Marseille, France; Service de pédiatrie multidisciplinaire, Hôpital de la Timone Enfants, APHM, 13385 Marseille, France. Electronic address: alexandre.fabre@univ-amu.fr.

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

PMID:
29429573
PMCID:
PMC5985364
DOI:
10.1016/j.ajhg.2018.01.009
[Indexed for MEDLINE]
Free PMC Article

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