6533b7ddfe1ef96bd1274ed4

RESEARCH PRODUCT

Characterization of variations responsible for neurodevelopmental disorders in the PTBP1 and PTBP2 genes

subject

description

Heterogeneous nuclear ribonucleoproteins (hnRNPs) polypyrimidine tract-binding protein 1 and 2 (PTBP1 and PTBP2) are splicing regulators, shuttling between nucleus and cytoplasm thanks to the action of partially overlapping nuclear localization and export signals (NLS and NES respectively). These two paralog proteins share similar RNA binding properties although they exhibit different expression levels and kinetics, post-translational modifications and cofactor interactions across tissues and cell types, thus regulating RNA metabolism in a cell- specific manner. Despite their fundamental role as alternative splicing factors implicated in cell growth, neuronal cell differentiation, and immune cells activation, little is known about their involvement in human disease.Here, we identified 25 individuals with de novo or inherited pathogenic start-loss or missense variants affecting either NLS or NLS/NES functions in PTBP1 (n=23) or PTBP2 (n=2), associated with osteochondrodysplasia and autism spectrum disorder with attention deficit hyperactivity disorder respectively. Intellectual functioning was variable across the whole cohort ranging from normal to moderately delayed. Epilepsy was reported in 3 out of 25 individuals. Using a combination of molecular genetics and transcriptomics approaches in patient-derivedfibroblasts and independent cellular and in vivo models, we demonstrated that pathogenic 86variants cause partial cytoplasmic retention and accumulation of PTBP1 and PTBP2 in processing bodies eventually causing alteration of mRNA stability without perturbing nuclear splicing. Overall, our data demonstrate that heterozygous pathogenic variants in PTBP1 and PTBP2 affecting their nucleocytoplasmic distribution are associated with developmental defects with or without intellectual disability.