De novo variants in NPTN cause a neurodevelopmental disorder with autism and neuroplastin-PMCA hypofunction

Abstract Background NPTN encodes human neuroplastin (hNp), a transmembrane immunoglobulin (Ig)-superfamily glycoprotein and a subunit of the plasma membrane calcium (Ca 2+ )-ATPases (PMCA). The critical importance of hNp and its associations with PMCA in the human brain remains unknown. Methods Here, we describe de novo NPTN variants in individuals with autism and mild-to-severe DD/ID and evaluate their effects using animal models and in silico, molecular, and cellular approaches. Results Four individuals present variants affecting the two hNp isoforms, hNp55 and hNp65. Other four variants affect only the hNp65 isoform. Two individuals independently carry the same loss-of-function nonsense variant, predicted to cause haploinsufficient production of all hNp isoforms. Haploinsufficient Nptn +/– mice displayed reduced levels of Np and PMCA and exhibited altered social behavior. Insufficient Np55/65 production in neurons resulted in reduced PMCA expression and function. Two missense variants caused particular structural and thermodynamic abnormalities and lower expression of hNps in human embryonic kidney (HEK) cells. In primary neurons, these hNp variants failed to regulate cytosolic Ca 2 ⁺ transients. In Drosophila , a missense mutation affecting the PMCA interaction failed to prevent the lethal phenotype caused by hNp ortholog elimination. Conclusions We show that a novel neurodevelopmental disorder characterized by intellectual disability and autism originates from haploinsufficient NPTN gene dosage or insufficient functionality of mutant hNp related to PMCA hypofunction.