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      Kinesin Kif3b mutation reduces NMDAR subunit NR 2A trafficking and causes schizophrenia‐like phenotypes in mice

      1 , 2 , 3 , 1 , 1 , 1 , 4 , 1 , 5

      The EMBO Journal

      EMBO

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          De novo mutations in schizophrenia implicate synaptic networks.

          Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case-control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders.
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            A polygenic burden of rare disruptive mutations in schizophrenia.

            Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.
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              Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.

              An in situ study of mRNAs encoding NMDA receptor subunits in the developing rat CNS revealed that, at all stages, the NR1 gene is expressed in virtually all neurons, whereas the four NR2 transcripts display distinct expression patterns. NR2B and NR2D mRNAs occur prenatally, whereas NR2A and NR2C mRNAs are first detected near birth. All transcripts except NR2D peak around P20. NR2D mRNA, present mainly in midbrain structures, peaks around P7 and thereafter decreases to adult levels. Postnatally, NR2B and NR2C transcript levels change in opposite directions in the cerebellar internal granule cell layer. In the adult hippocampus, NR2A and NR2B mRNAs are prominent in CA1 and CA3 pyramidal cells, but NR2C and NR2D mRNAs occur in different subsets of interneurons. Recombinant binary NR1-NR2 channels show comparable Ca2+ permeabilities, but marked differences in voltage-dependent Mg2+ block and in offset decay time constants. Thus, the distinct expression profiles and functional properties of NR2 subunits provide a basis for NMDA channel heterogeneity in the brain.
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                Author and article information

                Journal
                The EMBO Journal
                EMBO J
                EMBO
                0261-4189
                1460-2075
                November 21 2019
                January 02 2020
                November 20 2019
                January 02 2020
                : 39
                : 1
                Affiliations
                [1 ]Department of Cell Biology and Anatomy Graduate School of Medicine The University of Tokyo Tokyo Japan
                [2 ]Department of Biological Science Faculty of Sciences King Abdulaziz University Jeddah Saudi Arabia
                [3 ]Unit of Neurological Disorders Department of Genetic Medicine Faculty of Medicine Princess Al‐Jawhara Center of Excellence in Research of Hereditary Disorders (PACER.HD) King Abdulaziz University Jeddah Saudi Arabia
                [4 ]Department of Anatomy and Neuroscience Faculty of Medicine University of Tsukuba Tsukuba Ibaraki Japan
                [5 ]Center of Excellence in Genome Medicine Research King Abdulaziz University Jeddah Saudi Arabia
                Article
                10.15252/embj.2018101090
                © 2020

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                http://doi.wiley.com/10.1002/tdm_license_1.1

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