MassIVE MSV000096187

Complete Public PXD057134

Rescue of sexually dimorphic autistic-like abnormalities in mice carrying biallelic MDGA1 mutation by bazedoxifene

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Description

We understand that MDGA1 critically regulates GABAergic circuit disinhibition, but not whether and how MDGA1 dysfunction causes neurodevelopmental disorders. Here, we describe two patients with autism spectrum disorders (ASDs) carrying missense mutations in MDGA1: Val116Met/Ala688Val and Tyr635Cys/Glu756Gln. The Tyr635Cys/Glu751Gln substitution disrupts the triangular extracellular structure of MDGA1 and renders it unable to impact GABAergic synapses in hippocampal CA1 neurons. Murine in utero overexpression of MDGA1 Val116Met/Ala688Val alters normal cortical neuron migration and impairs ultrasonic vocalizations (USVs). Male Mdga1 knock-in (KI) mouse pups and adults harboring Tyr635Cys/Glu751Gln exhibit impaired USVs and sensorimotor gating, similar to male Mdga1 conditional knockout (cKO) mice. No behavioral deficit is seen in the females. Bazedoxifene (a selective estrogen receptor modulator) treatment of male Mdga1Y636C/E751Q KI mice restores the changes in expression and phosphorylation of a subset of GABAergic synaptic proteins, behaviors and GABAergic synaptic strength. Thus, different MDGA1 mutations manifest as distinct MDGA1 dysfunctions and likely cause ASDs via sexually dimorphic loss-of-function mechanisms. [doi:10.25345/C54M91N9N] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: MDGA1 ; Proteomics ; LC-MS/MS ; Autism spectrum disorders ; Phosphorylation ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Jin Young Kim, Korea Basic Science Institute, Rep. of Korea
Submitting User: yangyj
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