Abstract: Mounting evidence suggests that rare genetic variations contribute to the genetic risk for autism spectrum disorder (ASD). Here, we describe the first ASD-associated in-frame deletion in the human dopamine (DA) transporter (hDAT) gene. This mutation results in the deletion of the conserved Asn336 (∆N336). By integrating molecular insights from X-ray crystallography, electron paramagnetic resonance, and electrophysiology, we uncovered a conformational state of the transporter promoted by ∆N336. It is defined by a “half-open and inward-facing” conformation of the intracellular gate that leads to specific dysfunctions in DA homeostasis as determined in the brain of Drosophila melanogaster expressing hDAT ∆N336. Importantly, hDAT ∆N336 flies display increased fear and impaired social interactions, traits associated with DA dysfunction and ASD.
(PNAS February 26, 2019 116 (9) 3853-3862)