Clinical and functional heterogeneity associated with the disruption of Retinoic Acid Receptor beta
Véronique Caron
(1)
,
Nicolas Chassaing
(2, 3)
,
Nicola Ragge
(4, 5)
,
Felix Boschann
(6)
,
Angelina My-Hoa Ngu
(1)
,
Sarah Chorfi
(1)
,
Saquib A. Lakhani
(7)
,
Weizhen Ji
(7)
,
Laurie Steiner
(8)
,
Julien Marcadier
,
Philip R. Jansen
(9)
,
Laura A. van de Pol
(9)
,
Johanna M. van Hagen
(9)
,
Alvaro Serrano Russi
(10)
,
Gwenaël Le Guyader
(11)
,
Magnus Nordenskjöld
(12, 13)
,
Ann Nordgren
(12, 13)
,
Britt-Marie Anderlid
(12, 13)
,
Julie Plaisancié
(2, 3)
,
Corinna Stoltenburg
(6)
,
Denise Horn
(6)
,
Anne Drenckhahn
(6)
,
Fadi F. Hamdan
(14, 15)
,
Mathilde Lefebvre
(16)
,
Tania Attie-Bitach
(17)
,
Peggy Forey
(18)
,
Vasily Smirnov
(19)
,
Françoise Ernould
(20)
,
Marie-Line Jacquemont
(21)
,
Sarah Grotto
(16)
,
Alberto Alcantud
,
Alicia Coret
,
Rosario Ferrer-Avargues
,
Siddharth Srivastava
(22)
,
Catherine Vincent
(23, 24)
,
Shelby Romoser
(25)
,
Nicole Safina
(25)
,
Dimah Saade
(26)
,
James R. Lupski
(27, 28)
,
Daniel G. Calame
(27, 28)
,
David Geneviève
(29)
,
Nicolas Chatron
(30, 31)
,
Caroline Schluth-Bolard
(30)
,
Kenneth A. Myers
(32)
,
William B. Dobyns
(33)
,
Patrick Calvas
(3, 2)
,
Caroline Salmon
(34)
,
Richard Holt
(5)
,
Frances Elmslie
(35)
,
Marc Allaire
(36)
,
Daniil M. Prigozhin
(36)
,
André Tremblay
(1)
,
Jacques L. Michaud
(1)
1
Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada]
2 Service Génétique Médicale [CHU Toulouse]
3 Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale
4 Birmingham Women's and Children's NHS Foundation Trust
5 Oxford Brookes University
6 Charité - UniversitätsMedizin = Berlin University Medicine
7 Yale University [New Haven]
8 URMC - University of Rochester Medical Center
9 Amsterdam UMC - Amsterdam University Medical Centers
10 Children’s Hospital Los Angeles [Los Angeles]
11 Service de Génétique Médicale [CHU Poitiers]
12 Karolinska Institutet [Stockholm]
13 Karolinska University Hospital [Stockholm]
14 UdeM - Université de Montréal
15 CHU Sainte Justine [Montréal]
16 Hôpital Robert Debré Paris
17 Hôpital Necker - Enfants Malades [AP-HP]
18 CH Angoulême - Centre Hospitalier d'Angoulême
19 Service d’Exploration de la Vision et Neuro-ophtalmologie [CHU Lille]
20 Hôpital Claude Huriez [Lille]
21 CHU La Réunion - Centre Hospitalier Universitaire de La Réunion
22 Boston Children's Hospital
23 Hôpital Jeanne de Flandre [Lille]
24 RADEME - Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364
25 University of Iowa [Iowa City]
26 Carver College of Medicine, University of Iowa
27 BCM - Baylor College of Medicine
28 Texas Children's Hospital [Houston, USA]
29 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
30 HCL - Hospices Civils de Lyon
31 INMG-AR - Institut NeuroMyoGène - Appui à la recherche
32 McGill University = Université McGill [Montréal, Canada]
33 UMN - University of Minnesota System
34 NHS Royal Surrey - Royal Surrey County Hospital
35 St George’s University Hospitals
36 LBNL - Lawrence Berkeley National Laboratory [Berkeley]
2 Service Génétique Médicale [CHU Toulouse]
3 Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale
4 Birmingham Women's and Children's NHS Foundation Trust
5 Oxford Brookes University
6 Charité - UniversitätsMedizin = Berlin University Medicine
7 Yale University [New Haven]
8 URMC - University of Rochester Medical Center
9 Amsterdam UMC - Amsterdam University Medical Centers
10 Children’s Hospital Los Angeles [Los Angeles]
11 Service de Génétique Médicale [CHU Poitiers]
12 Karolinska Institutet [Stockholm]
13 Karolinska University Hospital [Stockholm]
14 UdeM - Université de Montréal
15 CHU Sainte Justine [Montréal]
16 Hôpital Robert Debré Paris
17 Hôpital Necker - Enfants Malades [AP-HP]
18 CH Angoulême - Centre Hospitalier d'Angoulême
19 Service d’Exploration de la Vision et Neuro-ophtalmologie [CHU Lille]
20 Hôpital Claude Huriez [Lille]
21 CHU La Réunion - Centre Hospitalier Universitaire de La Réunion
22 Boston Children's Hospital
23 Hôpital Jeanne de Flandre [Lille]
24 RADEME - Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364
25 University of Iowa [Iowa City]
26 Carver College of Medicine, University of Iowa
27 BCM - Baylor College of Medicine
28 Texas Children's Hospital [Houston, USA]
29 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
30 HCL - Hospices Civils de Lyon
31 INMG-AR - Institut NeuroMyoGène - Appui à la recherche
32 McGill University = Université McGill [Montréal, Canada]
33 UMN - University of Minnesota System
34 NHS Royal Surrey - Royal Surrey County Hospital
35 St George’s University Hospitals
36 LBNL - Lawrence Berkeley National Laboratory [Berkeley]
Julien Marcadier
- Fonction : Auteur
Alberto Alcantud
- Fonction : Auteur
Alicia Coret
- Fonction : Auteur
Rosario Ferrer-Avargues
- Fonction : Auteur
Résumé
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.
| Origine | Publication financée par une institution |
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