|Title||Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta.|
|Publication Type||Journal Article|
|Year of Publication||2023|
|Authors||Caron, 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 Authors||DDD study|
|Date Published||2023 Aug|
|Keywords||Humans, 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 Journal||Genet Med|
|Grant List||K23 NS119666 / NS / NINDS NIH HHS / United States |
/ DH_ / Department of Health / United Kingdom
T32 AI007526 / AI / NIAID NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States
WT098051 / WT_ / Wellcome Trust / United Kingdom
Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta.
|Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation. Genome Biol. 2023;24(1):269..|
|PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects. Am J Hum Genet. 2023;110(10):1787-1803..|
|Chimeric RNAs reveal putative neoantigen peptides for developing tumor vaccines for breast cancer. Front Immunol. 2023;14:1188831..|