GPATCH11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment: small non-coding RNA-seq data

We conducted a study involving 12 individuals with retinal dystrophy, neurological impairment and skeletal abnormalities placing special focus on GPATCH11, a lesser-known G-patch domain-containing protein regulator of RNA metabolism. To elucidate its role, we employed fibroblasts from unaffected individuals and patients carrying the recurring c.328+1G>T mutation, which specifically removes the main part of the G-patch domain while preserving the other domains. Additionally, we generated a mouse model replicating the patient's phenotyping defects, including retinal dystrophy and behavioral abnormalities. Our results revealed a subcellular localization characterized by a diffuse presence in the nucleoplasm, as well as centrosomal localization, suggesting roles in RNA and cilia metabolism. Transcriptomic analysis performed on mouse retina detected dysregulation in both gene expression and spliceosome 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 whose mutations are responsible for a new described syndrome.