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

TitleClinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta.
Publication TypeJournal Article
Year of Publication2023
AuthorsCaron, V, Chassaing, N, Ragge, N, Boschann, F, Ngu, AMy-Hoa, Meloche, E, Chorfi, S, Lakhani, SA, Ji, W, Steiner, L, Marcadier, J, Jansen, PR, van de Pol, LA, van Hagen, JM, Russi, ASerrano, Le Guyader, G, Nordenskjöld, M, Nordgren, A, Anderlid, B-M, Plaisancié, J, Stoltenburg, C, Horn, D, Drenckhahn, A, Hamdan, FF, Lefebvre, M, Attié-Bitach, T, Forey, P, Smirnov, V, Ernould, F, Jacquemont, M-L, Grotto, S, Alcantud, A, Coret, A, Ferrer-Avargues, R, Srivastava, S, Vincent-Delorme, C, Romoser, S, Safina, N, Saade, D, Lupski, JR, Calame, DG, Geneviève, D, Chatron, N, Schluth-Bolard, C, Myers, KA, Dobyns, WB, Calvas, P, Salmon, C, Holt, R, Elmslie, F, Allaire, M, Prigozhin, DM, Tremblay, A, Michaud, JL
Corporate AuthorsDDD study
JournalGenet Med
Date Published2023 Aug
KeywordsHumans, Microphthalmos, Receptors, Retinoic Acid, Retinoids

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.

Alternate JournalGenet Med
PubMed ID37092537
PubMed Central IDPMC10757562
Grant ListT32 GM007526 / GM / NIGMS NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
/ DH_ / Department of Health / United Kingdom
R35 NS105078 / NS / NINDS NIH HHS / United States
K23 NS119666 / NS / NINDS NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
T32 AI007526 / AI / NIAID NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States
WT098051 / WT_ / Wellcome Trust / United Kingdom

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