Autism-associated MDGA1 missense mutations impair distinct facets of central nervous system development
Kim, S.; Kim, H.; Pelayo, J. P.; Alvarez, S.; Jang, G.; Kim, J.; Hoelscher, V. M.; Calleja-Perez, B.; Jung, H.; Lee, J.; Kim, S.; de la Pena, M. J.; Han, A.-r.; Lee, D. S.; Ji, S.; Yu, W.; Kim, H. M.; An, J.-Y.; Oh, W. C.; Kwon, S.-K.; Um, J. W.; Fernandez-Jaen, A.; Ko, J.
Show abstract
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.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Oxytocin administration in neonates shapes the hippocampal circuitry and restores social behavior in a mouse model of autism. 98%
- Tbx1, a 22q11.2-encoded gene, is a link between alterations in fimbria myelination and cognitive speed in mice 97%
- Restoring Glutamate receptosome dynamics at synapses rescues Autism-like deficits in Shank3-deficient mice. 97%
Similar papers in this journal
- Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development 95%
- Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome 93%
- Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorders. 93%
Similar papers in this journal
- p75 neurotrophin receptor in pre-adolescent prefrontal PV interneurons promotes cognitive flexibility in adult mice 96%
- Developmental and behavioral phenotypes in a new mouse model of DDX3X syndrome 96%
- Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates 95%
Similar papers in this journal
- Partial or complete loss of norepinephrine differentially alters contextual fear and catecholamine release dynamics in hippocampal CA1 96%
- Modeling intrahippocampal effects of anterior hippocampal hyperactivity relevant to schizophrenia using chemogenetic excitation of long axis-projecting mossy cells in the mouse dentate gyrus 95%
- Multi-parametric assays capture sex- and environment-dependent modifiers of behavioral phenotypes in autism mouse models 94%
Similar papers in this journal
- Heterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice. 97%
- KIF2C regulates synaptic plasticity and cognition by mediating dynamic microtubule invasion of dendritic spines 96%
- Presynaptic Rac1 in the hippocampus selectively regulates working memory 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.