TY - JOUR
T1 - Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta
AU - DDD Study
AU - Caron, Véronique
AU - Chassaing, Nicolas
AU - Ragge, Nicola
AU - Boschann, Felix
AU - Ngu, Angelina My-Hoa
AU - Meloche, Elisabeth
AU - Chorfi, Sarah
AU - Lakhani, Saquib A
AU - Ji, Weizhen
AU - Steiner, Laurie
AU - Marcadier, Julien
AU - Jansen, Philip R
AU - van de Pol, Laura A
AU - van Hagen, Johanna M
AU - Russi, Alvaro Serrano
AU - Le Guyader, Gwenaël
AU - Nordenskjöld, Magnus
AU - Nordgren, Ann
AU - Anderlid, Britt-Marie
AU - Plaisancié, Julie
AU - Stoltenburg, Corinna
AU - Horn, Denise
AU - Drenckhahn, Anne
AU - Hamdan, Fadi F
AU - Lefebvre, Mathilde
AU - Attie-Bitach, Tania
AU - Forey, Peggy
AU - Smirnov, Vasily
AU - Ernould, Françoise
AU - Jacquemont, Marie-Line
AU - Grotto, Sarah
AU - Alcantud, Alberto
AU - Coret, Alicia
AU - Ferrer-Avargues, Rosario
AU - Srivastava, Siddharth
AU - Vincent-Delorme, Catherine
AU - Romoser, Shelby
AU - Safina, Nicole
AU - Saade, Dimah
AU - Lupski, James R
AU - Calame, Daniel G
AU - Geneviève, David
AU - Chatron, Nicolas
AU - Schluth-Bolard, Caroline
AU - Myers, Kenneth A
AU - Dobyns, William B
AU - Calvas, Patrick
AU - Salmon, Caroline
AU - Holt, Richard
AU - Elmslie, Frances
AU - The DDD Study
N1 - Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2023/8/1
Y1 - 2023/8/1
N2 - 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.
AB - 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.
KW - Dystonia
KW - Global developmental delay
KW - Humans
KW - Microphthalmia
KW - Microphthalmos
KW - Receptors, Retinoic Acid/genetics
KW - Retinoic acid
KW - Retinoic acid receptor beta
KW - Retinoids
UR - http://www.scopus.com/inward/record.url?scp=85161335560&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.gim.2023.100856
DO - https://doi.org/10.1016/j.gim.2023.100856
M3 - Article
C2 - 37092537
SN - 1098-3600
VL - 25
SP - 100856
JO - Genetics in medicine
JF - Genetics in medicine
IS - 8
M1 - 100856
ER -