ZFIN ID: ZDB-PUB-181212-28
Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia
Guissart, C., Latypova, X., Rollier, P., Khan, T.N., Stamberger, H., McWalter, K., Cho, M.T., Kjaergaard, S., Weckhuysen, S., Lesca, G., Besnard, T., Õunap, K., Schema, L., Chiocchetti, A.G., McDonald, M., de Bellescize, J., Vincent, M., Van Esch, H., Sattler, S., Forghani, I., Thiffault, I., Freitag, C.M., Barbouth, D.S., Cadieux-Dion, M., Willaert, R., Guillen Sacoto, M.J., Safina, N.P., Dubourg, C., Grote, L., Carré, W., Saunders, C., Pajusalu, S., Farrow, E., Boland, A., Karlowicz, D.H., Deleuze, J.F., Wojcik, M.H., Pressman, R., Isidor, B., Vogels, A., Van Paesschen, W., Al-Gazali, L., Al Shamsi, A.M., Claustres, M., Pujol, A., Sanders, S.J., Rivier, F., Leboucq, N., Cogné, B., Sasorith, S., Sanlaville, D., Retterer, K., Odent, S., Katsanis, N., Bézieau, S., Koenig, M., Davis, E.E., Pasquier, L., Küry, S.
Date: 2018
Source: American journal of human genetics   102: 744-759 (Journal)
Registered Authors: Davis, Erica, Katsanis, Nicholas
Keywords: RORA, autistic features, cerebellar ataxia, dual molecular effects, epilepsy, intellectual disability, neurodevelopmental disorder
MeSH Terms:
  • Adolescent
  • Adult
  • Aged, 80 and over
  • Alleles
  • Animals
  • Autistic Disorder/complications
  • Autistic Disorder/genetics*
  • Brain/pathology
  • Cerebellar Ataxia/complications
  • Cerebellar Ataxia/genetics*
  • Child
  • Child, Preschool
  • DNA Copy Number Variations/genetics
  • Disease Models, Animal
  • Female
  • Genes, Dominant*
  • Genetic Complementation Test
  • Humans
  • Intellectual Disability/complications
  • Intellectual Disability/genetics*
  • Larva/genetics
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Mutation, Missense/genetics*
  • Nuclear Receptor Subfamily 1, Group F, Member 1/genetics*
  • Purkinje Cells/metabolism
  • Purkinje Cells/pathology
  • Syndrome
  • Zebrafish/genetics
PubMed: 29656859 Full text @ Am. J. Hum. Genet.
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.