GPATCH11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment

Here we conduct a study involving 12 individuals with retinal dystrophy, neurological impairment, and skeletal abnormalities, with special focus on GPATCH11, a lesser-known G-patch domain-containing protein, regulator of RNA metabolism. To elucidate its role, we study fibroblasts from unaffected individuals and patients carrying the recurring c.328+1 G > T mutation, which specifically removes the main part of the G-patch domain while preserving the other domains. Additionally, we generate a mouse model replicating the patients' phenotypic defects, including retinal dystrophy and behavioral abnormalities. Our results reveal a subcellular localization of GPATCH11 characterized by a diffuse presence in the nucleoplasm, as well as centrosomal localization, suggesting potential functions in RNA and cilia metabolism. Transcriptomic analysis performed on mouse retina detect dysregulation in both gene expression and splicing activity, impacting key processes such as photoreceptor light responses, RNA regulation, and primary cilia-associated metabolism. Proteomic analysis of mouse retina confirms the roles GPATCH11 plays in RNA processing, splicing, and transcription regulation, while also suggesting additional functions in synaptic plasticity and nuclear stress response. Our research provides insights into the diverse roles of GPATCH11 and identifies that the mutations affecting this protein are responsible for a recently characterized described syndrome.

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Publication Details

Journal
Nature Communications
Published
2024-11-21
DOI
https://doi.org/10.1038/s41467-024-54549-8
Citations
4
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
0.94

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article

GPATCH11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment

Lucas Fares‐Taie, Nurit Assia Batzir, Efrat Sofrin, Carlo Rivolta et al.
4 citations
Nature Communications
RNA Research and Splicing
0.94
article

GPATCH11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment

Lucas Fares‐Taie, Nurit Assia Batzir, Efrat Sofrin, Carlo Rivolta, Jérôme E. Roger, Morgane Plutino, Ana Berta Sousa, Dinah Zur, Erwin L. van Dijk, Isabelle S. Audo, Paul Kuentz, Sylvain Briault, Pierre David, Jeanne Amiel, Luísa Coutinho Santos, Gwendal Dujardin, Danielle Amana, Sabine Sigaudy, Isabelle Perrault, Karolina Kamińska, Cristina Santos, Khaoula Zaafrane‐Khachnaoui, Nicole Philip-Sarles, Nathalie Boddaert, Nicolas Goudin, Ange‐Line Bruel, Mathieu Quinodoz, Jean‐Michel Rozet, Anat Bachar-Zipori, Matthieu P. Robert, Vincent Jung, Christel Thauvin‐Robinet, Lina Basel Salmon, Josseline Kaplan, Rui Sousa‐Luís, Ida Chiara Guerrera, Cyril Gitiaux, Naama Orenstein, Mariana Soeiro, Stéphanie Moriceau, Andrea Zanetti, Christine Costet-Fighiera
article en
4 citations

Abstract

Here we conduct a study involving 12 individuals with retinal dystrophy, neurological impairment, and skeletal abnormalities, with special focus on GPATCH11, a lesser-known G-patch domain-containing protein, regulator of RNA metabolism. To elucidate its role, we study fibroblasts from unaffected individuals and patients carrying the recurring c.328+1 G > T mutation, which specifically removes the main part of the G-patch domain while preserving the other domains. Additionally, we generate a mouse model replicating the patients' phenotypic defects, including retinal dystrophy and behavioral abnormalities. Our results reveal a subcellular localization of GPATCH11 characterized by a diffuse presence in the nucleoplasm, as well as centrosomal localization, suggesting potential functions in RNA and cilia metabolism. Transcriptomic analysis performed on mouse retina detect dysregulation in both gene expression and splicing activity, impacting key processes such as photoreceptor light responses, RNA regulation, and primary cilia-associated metabolism. Proteomic analysis of mouse retina confirms the roles GPATCH11 plays in RNA processing, splicing, and transcription regulation, while also suggesting additional functions in synaptic plasticity and nuclear stress response. Our research provides insights into the diverse roles of GPATCH11 and identifies that the mutations affecting this protein are responsible for a recently characterized described syndrome.

Nature CommunicationsVol. 15(1)
Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), University of Lisbon (PT), Transgene (France) (FR), University of Leicester (GB), Inserm (FR), Université de Bretagne Occidentale (FR), Tel Aviv University (IL), Université de Bourgogne (FR), University of Basel (CH), Université Paris Cité (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Tel Aviv Sourasky Medical Center (IL), Rabin Medical Center (IL), Centre hospitalier national d'ophtalmologie des Quinze-Vingts (FR), Centre Hospitalier Universitaire de Nice (FR), University of Oxford (GB), Institut des Neurosciences Paris-Saclay (FR), Institut des Maladies Neurodégénératives (FR), Assistance Publique – Hôpitaux de Paris (FR), Hôpital d'Enfants (FR), Institut de Biologie Intégrative de la Cellule (FR), Schneider Children's Medical Center (IL), Hôpital l'Archet (FR), CEA Paris-Saclay (FR), Centre Hospitalier Régional Universitaire de Brest (FR), Centre hospitalier universitaire d'Orléans (FR), Hospital de Santa Maria (PT), Hôpital de la Timone (FR), Institut des Maladies Génétiques Imagine (FR), Génétique, Génomique Fonctionnelle et Biotechnologies (FR), Institute of Molecular and Clinical Ophthalmology Basel (CH), Structure fédérative de recherche Necker (FR), Universidade Nova de Lisboa (PT)
National Science Foundation, Institut des maladies génétiques Imagine, European Commission, Agence Nationale de la Recherche, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Retina France, MSDAVENIR
Zero hunger
Openalex Percentile: Top 25%
RNA Research and Splicing
0.94
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