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Title: Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia
Author: Guissart, Claire
Latypova, Xenia
Rollier, Paul
Khan, Tahir N.
Stamberger, Hannah
McWalter, Kirsty
Cho, Megan T.
Kjaergaard, Susanne
Weckhuysen, Sarah
Lesca, Gaetan
Besnard, Thomas
Õunap, Katrin
Schema, Lynn
Chiocchetti, Andreas G.
Mcdonald, Marie
Bellescize, Julitta de
Vincent, Marie
Van Esch, Hilde
Sattler, Shannon
Forghani, Irman
Thiffault, Isabelle
Freitag, Christine M.
Barbouth, Deborah Sara
Cadieux-Dion, Maxime
Willaert, Rebecca
Guillen Sacoto, Maria J.
Safina, Nicole P.
Dubourg, Christèle
Grote, Lauren
Carre, Wilfrid
Saunders, Carol
Pajusalu, Sander
Farrow, Emily
Boland, Anne
Karlowicz, Danielle Hays
Deleuze, Jean-François
Wojcik, Monica H.
Pressman, Rena
Isidor, Bertrand
Vogels, Annick
Van Paesschen, Wim
Al-Gazali, Lihadh
Mohamed Al Shamsi, Aisha
Claustres, Mireille
Pujol Onofre, Aurora
Sanders, Stephan
Rivier, François
Leboucq, Nicolas
Cogne, Benjamin
Sasorith, Souphatta
Sanlaville, Damien
Retterer, Kyle
Odent, Sylvie
Katsanis, Nicholas
Bézieau, Stéphane
Koenig, Michel
Davis, Erica E.
Pasquier, Laurent
Küry, Sébastien
Keywords: Autisme
Malalties neurodegeneratives
Neurodegenerative diseases
Issue Date: 3-Jan-2018
Publisher: Cell Press
Abstract: ROR alpha, 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, mis sense 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.
Note: Versió postprint del document publicat a:
It is part of: American Journal of Human Genetics, 2018, vol. 102, num. 5, p. 744-759
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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