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

Spliceosome and ciliary dysfunctions can lead to remarkably similar clinical syndromes. Studying ten individuals with retinal dystrophy, neurological involvement, and skeletal abnormalities, suggestive of both spliceosomopathies and ciliopathies, we involved GPATCH11, a lesser-known GPATCH-domain-containing regulators of RNA metabolism. To elucidate GPATCH11 function, we employed fibroblasts from unaffected individuals and patients carrying a recurring mutation specifically removing the main part of the GPATCH-domain while preserving other domains. Additionally, we generated a mouse model replicating the patient’s genetic defect, exhibiting behavioural abnormalities and retinal dystrophy. Our findings revealed GPATCH11 unique subcellular localization, marked as foci staining pattern and a diffuse presence in the nucleoplasm, alongside its centrosomal localization, indicating roles in RNA and cilia metabolism. We show dysregulation of U4 snRNA in patient cells and dysregulation in both gene expression and spliceosome activity within the mutant mouse retina, impacting key processes such as photoreceptor light responses, RNA regulation, and primary cilia-associated metabolism. These results highlight GPATCH11 roles in RNA metabolism, spliceosome regulation, and potential ciliary involvement. They underscore its significance in maintaining proper gene expression, contributing to retinal, neurological, and skeletal functions. Our research also demonstrates how studying rare genetic disorders can reveal broader gene functions, providing insights into GPATCH11 multifaceted roles. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants from Retina France; Fondation JED Belgique; Fondation Visio to JMR and IP. Fondation des Aveugles de France, PhD international Institut Imagine to AZ. JMR is member of the European Reference Network for Rare Eye Diseases (ERN-EYE), which is co-funded by the Health Program of the European Union under the Framework Partnership Agreement n739534. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All individuals or legal representatives consented with the study, which received approval from the institutional review boards Comité de Protection des Personnes Ile de France II (Necker), Reference Center for Congenital Abnormalities and Malformative Syndromes in Dijon (France) and Orphonomix units for genetic testing, located in several hospitals in France. All participating individuals of Family 4 signed a consent form, in agreement with the Declaration of Helsinki and the ARVO statement on human subjects. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript