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Am J Hum Genet. 2018 May 3;102(5):744-759. doi: 10.1016/j.ajhg.2018.02.021. Epub 2018 Apr 12.

Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia.

Author information

1
EA7402 Institut Universitaire de Recherche Clinique, and Laboratoire de Génétique Moléculaire, CHU and Université de Montpellier, 34093 Montpellier, France.
2
Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA; l'institut du thorax, INSERM, CNRS, UNIV Nantes, 44007 Nantes, France.
3
Service de Génétique Clinique, Centre Référence "Déficiences Intellectuelles de causes rares" (CRDI), Centre de référence anomalies du développement CLAD-Ouest, CHU Rennes, 35203 Rennes, France.
4
Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
5
Division of Neurology, University Hospital Antwerp (UZA), 2610 Antwerp, Belgium; Neurogenetics Group, Center for Molecular Neurology, VIB, 2650 Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2650 Antwerp, Belgium.
6
GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
7
Chromosome Laboratory, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark.
8
Service de génétique, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France; INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
9
Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; l'institut du thorax, INSERM, CNRS, UNIV Nantes, 44007 Nantes, France.
10
Department of Clinical Genetics, United Laboratories, Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, 2 L.Puusepa street, Tartu 51014, Estonia.
11
University of Minnesota-Fairview, Minneapolis, MN 55454, USA.
12
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Deutschordenstraße 50, Frankfurt am Main 60528, Germany.
13
Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC 27710, USA.
14
Epilepsy, Sleep and Pediatric Neurophysiology Department, Hospices Civils, Lyon, 69677 Bron, France.
15
Center for Human Genetics, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.
16
Carle Physician Group, Urbana, IL 61801, USA.
17
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, 1501 NW 10th Avenue, BRB, room 359 (M-860), Miami, FL 33136, USA.
18
Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; University of Missouri Kansas City, School of Medicine, Kansas City, MO 64108, USA.
19
Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA.
20
University of Missouri Kansas City, School of Medicine, Kansas City, MO 64108, USA; Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA.
21
Laboratoire de Génétique Moléculaire & Génomique, CHU de Rennes, 35033 Rennes, France.
22
Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; University of Missouri Kansas City, School of Medicine, Kansas City, MO 64108, USA; Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, MO 64108, USA.
23
Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, DRF, CEA, Evry, France.
24
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
25
Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.
26
Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates.
27
Department of Paediatrics, Tawam Hospital, PO Box 15258, Al-Ain, United Arab Emirates.
28
Neurometabolic Diseases Laboratory, IDIBELL, Gran Via, 199, L'Hospitalet de Llobregat, 08908 Barcelona, and CIBERER U759, Center for Biomedical Research on Rare Diseases, 08908 Barcelona, Spain, Catalan Institution of Research and Advanced Studies (ICREA), 08010 Barcelona, Spain.
29
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
30
Department of Neuropaediatrics and CR Maladies Neuromusculaires, CHU Montpellier, PhyMedExp, INSERM, CNRS, University of Montpellier, Montpellier, France.
31
Neuroradiologie, CHU de Montpellier, 34090 Montpellier, France.
32
Service de Génétique Clinique, Centre Référence "Déficiences Intellectuelles de causes rares" (CRDI), Centre de référence anomalies du développement CLAD-Ouest, CHU Rennes, 35203 Rennes, France; CNRS UMR 6290, Université de Rennes, 2 Avenue du Professeur Léon Bernard, 35043 Rennes, France.
33
Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA. Electronic address: erica.davis@duke.edu.
34
Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; l'institut du thorax, INSERM, CNRS, UNIV Nantes, 44007 Nantes, France. Electronic address: sebastien.kury@chu-nantes.fr.

Abstract

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

KEYWORDS:

RORA; autistic features; cerebellar ataxia; dual molecular effects; epilepsy; intellectual disability; neurodevelopmental disorder

PMID:
29656859
PMCID:
PMC5986661
DOI:
10.1016/j.ajhg.2018.02.021
[Indexed for MEDLINE]
Free PMC Article

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