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

Publication ,  Journal Article
Guissart, C; Latypova, X; Rollier, P; Khan, TN; Stamberger, H; McWalter, K; Cho, MT; Kjaergaard, S; Weckhuysen, S; Lesca, G; Besnard, T ...
Published in: Am J Hum Genet
May 3, 2018

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.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

May 3, 2018

Volume

102

Issue

5

Start / End Page

744 / 759

Location

United States

Related Subject Headings

  • Zebrafish
  • Syndrome
  • Purkinje Cells
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Mutation, Missense
  • Middle Aged
  • Male
  • Magnetic Resonance Imaging
  • Larva
  • Intellectual Disability
 

Citation

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ICMJE
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Guissart, C., Latypova, X., Rollier, P., Khan, T. N., Stamberger, H., McWalter, K., … Küry, S. (2018). Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia. Am J Hum Genet, 102(5), 744–759. https://doi.org/10.1016/j.ajhg.2018.02.021
Guissart, Claire, Xenia Latypova, Paul Rollier, Tahir N. Khan, Hannah Stamberger, Kirsty McWalter, Megan T. Cho, et al. “Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia.Am J Hum Genet 102, no. 5 (May 3, 2018): 744–59. https://doi.org/10.1016/j.ajhg.2018.02.021.
Guissart C, Latypova X, Rollier P, Khan TN, Stamberger H, McWalter K, et al. Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia. Am J Hum Genet. 2018 May 3;102(5):744–59.
Guissart, Claire, et al. “Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia.Am J Hum Genet, vol. 102, no. 5, May 2018, pp. 744–59. Pubmed, doi:10.1016/j.ajhg.2018.02.021.
Guissart C, Latypova X, Rollier P, Khan TN, Stamberger H, McWalter K, Cho MT, Kjaergaard S, Weckhuysen S, Lesca G, Besnard T, Õunap K, Schema L, Chiocchetti AG, McDonald M, de Bellescize J, Vincent M, Van Esch H, Sattler S, Forghani I, Thiffault I, Freitag CM, Barbouth DS, Cadieux-Dion M, Willaert R, Guillen Sacoto MJ, Safina NP, Dubourg C, Grote L, Carré W, Saunders C, Pajusalu S, Farrow E, Boland A, Karlowicz DH, Deleuze J-F, Wojcik MH, Pressman R, Isidor B, Vogels A, Van Paesschen W, Al-Gazali L, Al Shamsi AM, Claustres M, Pujol A, Sanders SJ, Rivier F, Leboucq N, Cogné B, Sasorith S, Sanlaville D, Retterer K, Odent S, Katsanis N, Bézieau S, Koenig M, Davis EE, Pasquier L, Küry S. Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia. Am J Hum Genet. 2018 May 3;102(5):744–759.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

May 3, 2018

Volume

102

Issue

5

Start / End Page

744 / 759

Location

United States

Related Subject Headings

  • Zebrafish
  • Syndrome
  • Purkinje Cells
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Mutation, Missense
  • Middle Aged
  • Male
  • Magnetic Resonance Imaging
  • Larva
  • Intellectual Disability