Journal article
Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia
American journal of human genetics, Vol.102(5), pp.744-759
05/03/2018
DOI: 10.1016/j.ajhg.2018.02.021
PMCID: PMC5986661
PMID: 29656859
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.
Details
- Title: Subtitle
- Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia
- Creators
- Claire Guissart - Université de MontpellierXenia Latypova - Nantes UniversitéPaul Rollier - Service de Génétique Clinique, Centre Référence “Déficiences Intellectuelles de causes rares” (CRDI), Centre de référence anomalies du développement CLAD-Ouest, CHU Rennes, 35203 Rennes, FranceTahir N. Khan - Duke UniversityHannah Stamberger - University of AntwerpKirsty McWalter - GeneDxMegan T. Cho - GeneDxSusanne Kjaergaard - Copenhagen University HospitalSarah Weckhuysen - University of AntwerpGaetan Lesca - Hospices Civils de LyonThomas Besnard - Nantes UniversitéKatrin Õunap - Tartu University HospitalLynn Schema - University of MinnesotaAndreas G. Chiocchetti - Goethe University FrankfurtMarie McDonald - Duke UniversityJulitta de Bellescize - Epilepsy, Sleep and Pediatric Neurophysiology Department, Hospices Civils, Lyon, 69677 Bron, FranceMarie Vincent - Nantes UniversitéHilde Van Esch - KU LeuvenShannon Sattler - Urbana UniversityIrman Forghani - University of MiamiIsabelle Thiffault - University of Missouri–Kansas CityChristine M. Freitag - Goethe University FrankfurtDeborah Sara Barbouth - University of MiamiMaxime Cadieux-Dion - Children's Mercy HospitalRebecca Willaert - GeneDxMaria J. Guillen Sacoto - GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USANicole P. Safina - University of Missouri–Kansas CityChristèle Dubourg - Centre Hospitalier Universitaire de RennesLauren Grote - University of Missouri–Kansas CityWilfrid Carré - Centre Hospitalier Universitaire de RennesCarol Saunders - University of Missouri–Kansas CitySander Pajusalu - Tartu University HospitalEmily Farrow - University of Missouri–Kansas CityAnne Boland - Direction de la Recherche FondamentaleDanielle Hays Karlowicz - Duke UniversityJean-François Deleuze - Direction de la Recherche FondamentaleMonica H. Wojcik - Broad InstituteRena Pressman - University of MiamiBertrand Isidor - Nantes UniversitéAnnick Vogels - KU LeuvenWim Van Paesschen - KU LeuvenLihadh Al-Gazali - United Arab Emirates UniversityAisha Mohamed Al Shamsi - Tawam HospitalMireille Claustres - Université de MontpellierAurora Pujol - 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, SpainStephan J. Sanders - University of California, San FranciscoFrançois Rivier - Université de MontpellierNicolas Leboucq - Neuroradiologie, CHU de Montpellier, 34090 Montpellier, FranceBenjamin Cogné - Nantes UniversitéSouphatta Sasorith - Université de MontpellierDamien Sanlaville - Université Claude Bernard Lyon 1Kyle Retterer - GeneDxSylvie Odent - Université de RennesNicholas Katsanis - Duke UniversityStéphane Bézieau - Nantes UniversitéMichel Koenig - Université de MontpellierErica E. Davis - Duke UniversityLaurent Pasquier - Service de Génétique Clinique, Centre Référence “Déficiences Intellectuelles de causes rares” (CRDI), Centre de référence anomalies du développement CLAD-Ouest, CHU Rennes, 35203 Rennes, FranceSébastien Küry - Nantes Université
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.102(5), pp.744-759
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.ajhg.2018.02.021
- PMID
- 29656859
- PMCID
- PMC5986661
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Grant note
- name: Agence Nationale pour la Recherche/E-rare Joint-Transnational-Call 2011, award: 2011-RARE-004-01; DOI: 10.13039/100000051, name: National Human Genome Research Institute; name: National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program; DOI: 10.13039/100000053, name: National Eye Institute, award: UM1 HG008900; name: NIH, award: T32 HD07466; name: NIH, award: R01 MH106826; DOI: 10.13039/501100002301, name: Estonian Research Council, award: PUT355
- Language
- English
- Date published
- 05/03/2018
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984353943402771
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