TY - JOUR T1 - Functional and structural deficiencies of Gemin5 variants associated with neurological disorders JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201403 VL - 5 IS - 7 SP - e202201403 AU - Rosario Francisco-Velilla AU - Azman Embarc-Buh AU - Francisco del Caño-Ochoa AU - Salvador Abellan AU - Marçal Vilar AU - Sara Alvarez AU - Alberto Fernandez-Jaen AU - Sukhleen Kour AU - Deepa S Rajan AU - Udai Bhan Pandey AU - Santiago Ramón-Maiques AU - Encarnacion Martinez-Salas Y1 - 2022/07/01 UR - https://www.life-science-alliance.org/content/5/7/e202201403.abstract N2 - Dysfunction of RNA-binding proteins is often linked to a wide range of human disease, particularly with neurological conditions. Gemin5 is a member of the survival of the motor neurons (SMN) complex, a ribosome-binding protein and a translation reprogramming factor. Recently, pathogenic mutations in Gemin5 have been reported, but the functional consequences of these variants remain elusive. Here, we report functional and structural deficiencies associated with compound heterozygosity variants within the Gemin5 gene found in patients with neurodevelopmental disorders. These clinical variants are located in key domains of Gemin5, the tetratricopeptide repeat (TPR)–like dimerization module and the noncanonical RNA-binding site 1 (RBS1). We show that the TPR-like variants disrupt protein dimerization, whereas the RBS1 variant confers protein instability. All mutants are defective in the interaction with protein networks involved in translation and RNA-driven pathways. Importantly, the TPR-like variants fail to associate with native ribosomes, hampering its involvement in translation control and establishing a functional difference with the wild-type protein. Our study provides insights into the molecular basis of disease associated with malfunction of the Gemin5 protein. ER -