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Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia
- Source :
- American Journal of Human Genetics, American Journal of Human Genetics, Elsevier (Cell Press), 2018, 102 (5), pp.744-759. ⟨10.1016/j.ajhg.2018.02.021⟩, Dipòsit Digital de la UB, Universidad de Barcelona, The American journal of human genetics, American Journal of Human Genetics, 2018, 102 (5), pp.744-759. ⟨10.1016/j.ajhg.2018.02.021⟩, American journal of human genetics, vol 102, iss 5
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
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. ispartof: American Journal of Human Genetics vol:102 issue:5 pages:744-759 ispartof: location:United States status: published
- Subjects :
- Male
0301 basic medicine
Autism
[SDV]Life Sciences [q-bio]
Neurodegenerative
Medical and Health Sciences
RORA
Purkinje Cells
0302 clinical medicine
Neurodevelopmental disorder
Group F
80 and over
2.1 Biological and endogenous factors
Missense mutation
Aetiology
Child
Zebrafish
ComputingMilieux_MISCELLANEOUS
Genetics (clinical)
Genes, Dominant
Pediatric
Genetics & Heredity
Aged, 80 and over
Genetics
Malalties neurodegeneratives
Brain
Nuclear Receptor Subfamily 1, Group F, Member 1
Neurodegenerative Diseases
Syndrome
Biological Sciences
Middle Aged
Magnetic Resonance Imaging
3. Good health
Mental Health
intellectual disability
Child, Preschool
Larva
Neurological
Female
Cerebellar atrophy
medicine.symptom
Haploinsufficiency
Adult
Member 1
Ataxia
Cerebellar Ataxia
Nuclear Receptor Subfamily 1
Adolescent
DNA Copy Number Variations
Intellectual and Developmental Disabilities (IDD)
Mutation, Missense
Biology
Article
03 medical and health sciences
Rare Diseases
medicine
Animals
Humans
Dominant
Autistic Disorder
Allele
Preschool
Alleles
Aged
[SDV.GEN]Life Sciences [q-bio]/Genetics
Cerebellar ataxia
Animal
Point mutation
Genetic Complementation Test
Neurosciences
medicine.disease
neurodevelopmental disorder
Brain Disorders
Disease Models, Animal
030104 developmental biology
Genes
autistic features
Disease Models
Mutation
epilepsy
Human medicine
cerebellar ataxia
Missense
Autisme
dual molecular effects
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 00029297 and 15376605
- Volume :
- 102
- Database :
- OpenAIRE
- Journal :
- The American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....1c4e5c340742bf73c530ddc48aa0dec0