Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta.

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  • Additional Information
    • Corporate Authors:
      DDD Study; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 9815831 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1530-0366 (Electronic) Linking ISSN: 10983600 NLM ISO Abbreviation: Genet Med Subsets: MEDLINE
    • Publication Information:
      Publication: 2022- : [New York] : Elsevier
      Original Publication: Baltimore, MD : Lippincott, Williams & Wilkins, c1998-
    • Subject Terms:
      Receptors, Retinoic Acid*/genetics ; Receptors, Retinoic Acid*/metabolism ; Microphthalmos*; Humans ; Retinoids
    • Abstract:
      Purpose: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.
      Methods: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids.
      Results: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment.
      Conclusion: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.
      Competing Interests: Conflict of Interest J.R.L. owns stock in 23andMe and is a paid consultant for Genome International. All other authors declare no conflicts of interest.
      (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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    • Grant Information:
      T32 GM007526 United States GM NIGMS NIH HHS; UL1 TR001863 United States TR NCATS NIH HHS; United Kingdom DH_ Department of Health; R35 NS105078 United States NS NINDS NIH HHS; K23 NS119666 United States NS NINDS NIH HHS; United Kingdom WT_ Wellcome Trust; T32 AI007526 United States AI NIAID NIH HHS; U01 HG011758 United States HG NHGRI NIH HHS; WT098051 United Kingdom WT_ Wellcome Trust
    • Contributed Indexing:
      Keywords: Dystonia; Global developmental delay; Microphthalmia; Retinoic acid; Retinoic acid receptor beta
    • Accession Number:
      0 (retinoic acid receptor beta)
      0 (Receptors, Retinoic Acid)
      0 (Retinoids)
    • Publication Date:
      Date Created: 20230424 Date Completed: 20230807 Latest Revision: 20240802
    • Publication Date:
      20240802
    • Accession Number:
      PMC10757562
    • Accession Number:
      10.1016/j.gim.2023.100856
    • Accession Number:
      37092537