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


ABSTRACT: ROR?, 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.

SUBMITTER: Guissart C 

PROVIDER: S-EPMC5986661 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Guissart Claire C   Latypova Xenia X   Rollier Paul P   Khan Tahir N TN   Stamberger Hannah H   McWalter Kirsty K   Cho Megan T MT   Kjaergaard Susanne S   Weckhuysen Sarah S   Lesca Gaetan G   Besnard Thomas T   Õunap Katrin K   Schema Lynn L   Chiocchetti Andreas G AG   McDonald Marie M   de Bellescize Julitta J   Vincent Marie M   Van Esch Hilde H   Sattler Shannon S   Forghani Irman I   Thiffault Isabelle I   Freitag Christine M CM   Barbouth Deborah Sara DS   Cadieux-Dion Maxime M   Willaert Rebecca R   Guillen Sacoto Maria J MJ   Safina Nicole P NP   Dubourg Christèle C   Grote Lauren L   Carré Wilfrid W   Saunders Carol C   Pajusalu Sander S   Farrow Emily E   Boland Anne A   Karlowicz Danielle Hays DH   Deleuze Jean-François JF   Wojcik Monica H MH   Pressman Rena R   Isidor Bertrand B   Vogels Annick A   Van Paesschen Wim W   Al-Gazali Lihadh L   Al Shamsi Aisha Mohamed AM   Claustres Mireille M   Pujol Aurora A   Sanders Stephan J SJ   Rivier François F   Leboucq Nicolas N   Cogné Benjamin B   Sasorith Souphatta S   Sanlaville Damien D   Retterer Kyle K   Odent Sylvie S   Katsanis Nicholas N   Bézieau Stéphane S   Koenig Michel M   Davis Erica E EE   Pasquier Laurent L   Küry Sébastien S  

American journal of human genetics 20180412 5


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 ge  ...[more]

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