De novo variants in NPTN cause a neurodevelopmental disorder with autism and neuroplastin-PMCA hypofunction
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NPTN encodes human neuroplastin (hNp), a subunit of plasma membrane Ca 2+ -ATPases (PMCA). The critical importance of hNp and its associations with PMCA are unknown for the human brain. Here, we describe de novo NPTN variants in seven individuals with autism and mild-to-severe DD/ID and evaluate them using animal models and in silico , molecular and cellular approaches. We identified NPTN variants with dominant-negative (missense) or loss-of-function (nonsense/ frameshift) effect on hNp-PMCA expression and function. The missense variants caused structural and thermodynamic molecular abnormalities and lower expression of hNp in HEK cells. In neurons, hNp missense variants affected PMCA levels and cytosolic Ca²⁺ regulation. In Drosophila , a missense mutation with affected PMCA interaction failed to prevent a lethal phenotype caused by hNp ortholog elimination. In Nptn +/− mice, levels of Np and PMCA were reduced and insufficient for normal social behavior. Therefore, we show that de novo variants in NPTN cause a neurodevelopmental disorder with intellectual disability and autism, likely linked to PMCA dysfunction.
