Autism-associated MDGA1 missense mutations impair distinct facets of central nervous system development
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MDGA1 reportedly suppresses GABAergic synaptic inhibition, but it is unclear whether and how MDGA1 dysfunction causes neurodevelopmental disorders. Here, we describe two patients with autism spectrum disorders (ASDs) each carrying pairs of novel missense mutations in MDGA1 , Val116Met/Ala688Val and Tyr635Cys/Glu756Gln. The Tyr635Cys/Glu756Gln substitution (but not the Val116Met/Ala688V substitution) disrupts the triangular extracellular structure of MDGA1 and renders it unable to impact GABAergic synapses in both cultured hippocampal neurons and hippocampal CA1 pyramidal neurons. Conversely, murine in utero overexpression of MDGA1 Val116Met/Ala688Val alters normal cortical neuron migration and impairs ultrasonic vocalizations. Extensive behavioral analyses using forebrain-specific Mdga1 conditional knockout adult mice revealed a subset of behavioral deficits reminiscent of ASD animal models. Our results collectively demonstrate that different pairs of MDGA1 missense variants associated with ASDs impair distinct facets of central nervous system development via loss-of-function mechanisms.
