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.
Original language | English (US) |
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Pages (from-to) | 744-759 |
Number of pages | 16 |
Journal | American journal of human genetics |
Volume | 102 |
Issue number | 5 |
DOIs | |
State | Published - May 3 2018 |
Funding
We are grateful to Dr. R. Hawkes and Dr. C. Armstrong (University of Calgary) for providing the zebrin II antibody. We also thank Mr. Z. Kupchinsky for zebrafish husbandry, Mr. D. Morrow for assisting with reagents for the in vivo modeling study, and members of the Center for Human Disease Modeling for helpful comments. We are also grateful to Ms. J.A. Rosenfeld (Mokry) for her precious help in our search for similar affected individuals and for her review of the manuscript. This work was supported by funds from the Agence Nationale pour la Recherche/E-rare Joint-Transnational-Call 2011 ( 2011-RARE-004-01 “Euro-SCAR”) to M.K.; from the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute (to the Broad Center for Mendelian Genomics [ UM1 HG008900 ]); from the NIH grant T32 HD07466 (to M.H.W.); US NIH grant R01 MH106826 to E.E.D.; and from the Estonian Research Council , grant PUT355 (to S.P. and K.Õ.). We also acknowledge the Deciphering Developmental Disorders (DDD) Study. We are grateful to Dr. R. Hawkes and Dr. C. Armstrong (University of Calgary) for providing the zebrin II antibody. We also thank Mr. Z. Kupchinsky for zebrafish husbandry, Mr. D. Morrow for assisting with reagents for the in vivo modeling study, and members of the Center for Human Disease Modeling for helpful comments. We are also grateful to Ms. J.A. Rosenfeld (Mokry) for her precious help in our search for similar affected individuals and for her review of the manuscript. This work was supported by funds from the Agence Nationale pour la Recherche/E-rare Joint-Transnational-Call 2011 (2011-RARE-004-01 ?Euro-SCAR?) to M.K.; from the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute (to the Broad Center for Mendelian Genomics [UM1 HG008900]); from the NIH grant T32 HD07466 (to M.H.W.); US NIH grant R01 MH106826 to E.E.D.; and from the Estonian Research Council, grant PUT355 (to S.P. and K.?.). We also acknowledge the Deciphering Developmental Disorders (DDD) Study.
Keywords
- RORA
- autistic features
- cerebellar ataxia
- dual molecular effects
- epilepsy
- intellectual disability
- neurodevelopmental disorder
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)