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A unique binding mode of the eukaryotic translation initiation factor 4E for guiding the design of novel peptide inhibitors.

June 9, 2016 - 5:51pm
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A unique binding mode of the eukaryotic translation initiation factor 4E for guiding the design of novel peptide inhibitors.

Protein Sci. 2015 Sep;24(9):1370-82

Authors: Di Marino D, D'Annessa I, Tancredi H, Bagni C, Gallicchio E

Abstract
The interaction between the eukaryotic translation initiation factor 4E (eIF4E) and eIF4E binding proteins (4E-BP) is a promising template for the inhibition of eIF4E and the treatment of diseases such as cancer and a spectrum of autism disorders, including the Fragile X syndrome (FXS). Here, we report an atomically detailed model of the complex between eIF4E and a peptide fragment of a 4E-BP, the cytoplasmic Fragile X interacting protein (CYFIP1). This model was generated using computer simulations with enhanced sampling from an alchemical replica exchange approach and validated using long molecular dynamics simulations. 4E-BP proteins act as post-transcriptional regulators by binding to eIF4E and preventing mRNA translation. Dysregulation of eIF4E activity has been linked to cancer, FXS, and autism spectrum disorders. Therefore, the study of the mechanism of inhibition of eIF4E by 4E-BPs is key to the development of drug therapies targeting this regulatory pathways. The results obtained in this work indicate that CYFIP1 interacts with eIF4E by an unique mode not shared by other 4E-BP proteins and elucidate the mechanism by which CYFIP1 interacts with eIF4E despite having a sequence binding motif significantly different from most 4E-BPs. Our study suggests an alternative strategy for the design of eIF4E inhibitor peptides with superior potency and specificity than currently available.

PMID: 26013047 [PubMed - indexed for MEDLINE]

NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse.

June 9, 2016 - 5:51pm
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NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse.

Mol Psychiatry. 2015 Sep;20(9):1120-31

Authors: Schuster S, Rivalan M, Strauss U, Stoenica L, Trimbuch T, Rademacher N, Parthasarathy S, Lajkó D, Rosenmund C, Shoichet SA, Winter Y, Tarabykin V, Rosário M

Abstract
Neuropsychiatric developmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia, are typically characterized by alterations in social behavior and have been linked to aberrant dendritic spine and synapse development. Here we show, using genetically engineered mice, that the Cdc42 GTPase-activating multiadaptor protein, NOMA-GAP, regulates autism-like social behavior in the mouse, as well as dendritic spine and synapse development. Surprisingly, we were unable to restore spine morphology or autism-associated social behavior in NOMA-GAP-deficient animals by Cre-mediated deletion of Cdc42 alone. Spine morphology can be restored in vivo by re-expression of wild-type NOMA-GAP or a mutant of NOMA-GAP that lacks the RhoGAP domain, suggesting that other signaling functions are involved. Indeed, we show that NOMA-GAP directly interacts with several MAGUK (membrane-associated guanylate kinase) proteins, and that this modulates NOMA-GAP activity toward Cdc42. Moreover, we demonstrate that NOMA-GAP is a major regulator of PSD-95 in the neocortex. Loss of NOMA-GAP leads to strong upregulation of serine 295 phosphorylation of PSD-95 and moreover to its subcellular mislocalization. This is associated with marked loss of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and defective synaptic transmission, thereby providing a molecular basis for autism-like social behavior in the absence of NOMA-GAP.

PMID: 25869807 [PubMed - indexed for MEDLINE]

Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.

June 9, 2016 - 5:51pm
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Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.

Mol Psychiatry. 2015 Sep;20(9):1069-78

Authors: Oguro-Ando A, Rosensweig C, Herman E, Nishimura Y, Werling D, Bill BR, Berg JM, Gao F, Coppola G, Abrahams BS, Geschwind DH

Abstract
Rare maternally inherited duplications at 15q11-13 are observed in ~1% of individuals with an autism spectrum disorder (ASD), making it among the most common causes of ASD. 15q11-13 comprises a complex region, and as this copy number variation encompasses many genes, it is important to explore individual genotype-phenotype relationships. Cytoplasmic FMR1-interacting protein 1 (CYFIP1) is of particular interest because of its interaction with Fragile X mental retardation protein (FMRP), its upregulation in transformed lymphoblastoid cell lines from patients with duplications at 15q11-13 and ASD and the presence of smaller overlapping deletions of CYFIP1 in patients with schizophrenia and intellectual disability. Here, we confirm that CYFIP1 is upregulated in transformed lymphoblastoid cell lines and demonstrate its upregulation in the post-mortem brain from 15q11-13 duplication patients for the first time. To investigate how increased CYFIP1 dosage might predispose to neurodevelopmental disease, we studied the consequence of its overexpression in multiple systems. We show that overexpression of CYFIP1 results in morphological abnormalities including cellular hypertrophy in SY5Y cells and differentiated mouse neuronal progenitors. We validate these results in vivo by generating a BAC transgenic mouse, which overexpresses Cyfip1 under the endogenous promotor, observing an increase in the proportion of mature dendritic spines and dendritic spine density. Gene expression profiling on embryonic day 15 suggested the dysregulation of mammalian target of rapamycin (mTOR) signaling, which was confirmed at the protein level. Importantly, similar evidence of mTOR-related dysregulation was seen in brains from 15q11-13 duplication patients with ASD. Finally, treatment of differentiated mouse neuronal progenitors with an mTOR inhibitor (rapamycin) rescued the morphological abnormalities resulting from CYFIP1 overexpression. Together, these data show that CYFIP1 overexpression results in specific cellular phenotypes and implicate modulation by mTOR signaling, further emphasizing its role as a potential convergent pathway in some forms of ASD.

PMID: 25311365 [PubMed - indexed for MEDLINE]

Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.

June 9, 2016 - 5:51pm
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Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.

Mol Psychiatry. 2015 Sep;20(9):1132-8

Authors: Frazier TW, Embacher R, Tilot AK, Koenig K, Mester J, Eng C

Abstract
PTEN is a tumor suppressor associated with an inherited cancer syndrome and an important regulator of ongoing neural connectivity and plasticity. The present study examined molecular and phenotypic characteristics of individuals with germline heterozygous PTEN mutations and autism spectrum disorder (ASD) (PTEN-ASD), with the aim of identifying pathophysiologic markers that specifically associate with PTEN-ASD and that may serve as targets for future treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14). Group differences were evaluated for PTEN pathway protein expression levels, global and regional structural brain volumes and cortical thickness measures, neurocognition and adaptive behavior. RNA expression patterns and brain characteristics of a murine model of Pten mislocalization were used to further evaluate abnormalities observed in human PTEN-ASD patients. PTEN-ASD had a high proportion of missense mutations and showed reduced PTEN protein levels. Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory. White-matter abnormalities mediated the relationship between PTEN protein reductions and reduced cognitive ability. The Pten(m3m4) murine model had differential expression of genes related to myelination and increased corpus callosum. Processing speed and working memory deficits and white-matter abnormalities may serve as useful features that signal clinicians that PTEN is etiologic and prompting referral to genetic professionals for gene testing, genetic counseling and cancer risk management; and could reveal treatment targets in trials of treatments for PTEN-ASD.

PMID: 25288137 [PubMed - indexed for MEDLINE]

Autism, DRD3 and repetitive and stereotyped behavior, an overview of the current knowledge.

June 9, 2016 - 5:51pm
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Autism, DRD3 and repetitive and stereotyped behavior, an overview of the current knowledge.

Eur Neuropsychopharmacol. 2015 Sep;25(9):1421-6

Authors: Staal WG

Abstract
The SNP rs167771 of the dopamine-3-receptor gene (DRD3) has been associated with autism spectrum disorder (ASD) in samples from the United Kingdom, The Netherlands and Spain. The DRD3 polymorphisms of rs167771 are significantly associated with a specific type of repetitive and stereotyped behavior, called sameness. Repetitive and stereotyped behavior occurs in several neuropsychiatric disorders and the combined picture across these disorders strongly suggests the involvement of the basal ganglia - frontal lobe circuitry. In autism, abnormalities of the basal ganglia, in particular the caudate nucleus, are the best replicated findings in neuroimaging studies. Interestingly, the DRD3 gene is highly expressed in the basal ganglia, most notably the caudate nucleus. The rs167771 SNP was recently also found to be related to risperidone-induced extra-pyramidal side effects (EPS) in patients with autism, which is important since risperidone is approved for the treatment of aggression, irritability and rigid behavior in ASD. To conclude, striatum abnormalities in autism are associated with repetitive and stereotyped behavior in autism and may be related to DRD3 polymorphisms.

PMID: 25224105 [PubMed - indexed for MEDLINE]

ELAVL2-regulated transcriptional and splicing networks in human neurons link neurodevelopment and autism.

June 5, 2016 - 8:29am
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ELAVL2-regulated transcriptional and splicing networks in human neurons link neurodevelopment and autism.

Hum Mol Genet. 2016 Jun 3;

Authors: Berto S, Usui N, Konopka G, Fogel BL

Abstract
The role of post-transcriptional gene regulation in human brain development and neurodevelopmental disorders remains mostly uncharacterized. ELAV-like RNA-binding proteins are a family of proteins that regulate several aspects of neuronal function including neuronal excitability and synaptic transmission, both critical to the normal function of the brain in cognition and behavior. Here, we identify the downstream neuronal transcriptional and splicing networks of ELAVL2, an RNA-binding protein with previously unknown function in the brain. Expression of ELAVL2 was reduced in human neurons and RNA-sequencing was utilized to identify networks of differentially expressed and alternatively spliced genes resulting from haploinsufficient levels of ELAVL2. These networks contain a number of autism-relevant genes as well as previously identified targets of other important RNA-binding proteins implicated in autism spectrum disorder including RBFOX1 and FMRP. ELAVL2-regulated co-expression networks are also enriched for neurodevelopmental and synaptic genes, and include genes with human-specific patterns of expression in the frontal pole. Together, these data suggest that ELAVL2 regulation of transcript expression is critical for neuronal function and clinically relevant to autism spectrum disorder.

PMID: 27260404 [PubMed - as supplied by publisher]

DNA Damage and Repair in Schizophrenia and Autism: Implications for Cancer Comorbidity and Beyond.

June 4, 2016 - 5:28pm

DNA Damage and Repair in Schizophrenia and Autism: Implications for Cancer Comorbidity and Beyond.

Int J Mol Sci. 2016;17(6)

Authors: Markkanen E, Meyer U, Dianov GL

Abstract
Schizophrenia and autism spectrum disorder (ASD) are multi-factorial and multi-symptomatic psychiatric disorders, each affecting 0.5%-1% of the population worldwide. Both are characterized by impairments in cognitive functions, emotions and behaviour, and they undermine basic human processes of perception and judgment. Despite decades of extensive research, the aetiologies of schizophrenia and ASD are still poorly understood and remain a significant challenge to clinicians and scientists alike. Adding to this unsatisfactory situation, patients with schizophrenia or ASD often develop a variety of peripheral and systemic disturbances, one prominent example of which is cancer, which shows a direct (but sometimes inverse) comorbidity in people affected with schizophrenia and ASD. Cancer is a disease characterized by uncontrolled proliferation of cells, the molecular origin of which derives from mutations of a cell's DNA sequence. To counteract such mutations and repair damaged DNA, cells are equipped with intricate DNA repair pathways. Oxidative stress, oxidative DNA damage, and deficient repair of oxidative DNA lesions repair have been proposed to contribute to the development of schizophrenia and ASD. In this article, we summarize the current evidence of cancer comorbidity in these brain disorders and discuss the putative roles of oxidative stress, DNA damage and DNA repair in the aetiopathology of schizophrenia and ASD.

PMID: 27258260 [PubMed - as supplied by publisher]

A spectral approach integrating functional genomic annotations for coding and noncoding variants.

June 4, 2016 - 5:28pm
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A spectral approach integrating functional genomic annotations for coding and noncoding variants.

Nat Genet. 2016 Feb;48(2):214-20

Authors: Ionita-Laza I, McCallum K, Xu B, Buxbaum JD

Abstract
Over the past few years, substantial effort has been put into the functional annotation of variation in human genome sequences. Such annotations can have a critical role in identifying putatively causal variants for a disease or trait among the abundant natural variation that occurs at a locus of interest. The main challenges in using these various annotations include their large numbers and their diversity. Here we develop an unsupervised approach to integrate these different annotations into one measure of functional importance (Eigen) that, unlike most existing methods, is not based on any labeled training data. We show that the resulting meta-score has better discriminatory ability using disease-associated and putatively benign variants from published studies (in both coding and noncoding regions) than the recently proposed CADD score. Across varied scenarios, the Eigen score performs generally better than any single individual annotation, representing a powerful single functional score that can be incorporated in fine-mapping studies.

PMID: 26727659 [PubMed - indexed for MEDLINE]

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior.

June 4, 2016 - 5:28pm
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Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior.

Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):E6964-72

Authors: Li J, Chai A, Wang L, Ma Y, Wu Z, Yu H, Mei L, Lu L, Zhang C, Yue W, Xu L, Rao Y, Zhang D

Abstract
Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1α (protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs.

PMID: 26621702 [PubMed - indexed for MEDLINE]

[Molecular Biology on the Mechanisms of Autism Spectrum Disorder for Clinical Psychiatrists].

June 3, 2016 - 8:24am
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[Molecular Biology on the Mechanisms of Autism Spectrum Disorder for Clinical Psychiatrists].

Seishin Shinkeigaku Zasshi. 2015;117(10):862-8

Authors: Makinodan M

Abstract
While, in general, a certain number of clinical psychiatrists might not be familiar with molecular biology, the mechanisms of mental illnesses have been uncovered by molecular biology for decades. Among mental illnesses, even biological psychiatrists and neuroscientists have paid less attention to the biological treatment of autism spectrum disorder (ASD) than Alzheimer's disease and schizophrenia since ASD has been regarded as a developmental disorder that was seemingly untreatable. However, multifaceted methods of molecular biology have revealed the mechanisms that would lead to the medication of ASD. In this article, how molecular biology dissects the pathobiology of ASD is described in order to announce the possibilities of biological treatment for clinical psychiatrists.

PMID: 26827412 [PubMed - indexed for MEDLINE]

Autism cornered: network analyses reveal mechanisms of autism spectrum disorders.

June 3, 2016 - 8:24am
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Autism cornered: network analyses reveal mechanisms of autism spectrum disorders.

Mol Syst Biol. 2014;10:778

Authors: Auffray C

Abstract
Despite a wealth of behavioral, cognitive,biological, and genetic studies, the causes of autism have remained largely unknown.In their recent work, Snyder and colleagues(Li et al, 2014) use a systems biology approach and shed light on the molecular and cellular mechanisms underlying autism, thus opening novel avenues forunderstanding the disease and developing potential treatments.

PMID: 25549969 [PubMed - indexed for MEDLINE]

Recent Advances in Autism Spectrum Disorders: Applications of Whole Exome Sequencing Technology.

June 2, 2016 - 8:19am
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Recent Advances in Autism Spectrum Disorders: Applications of Whole Exome Sequencing Technology.

Psychiatry Investig. 2016 May;13(3):255-64

Authors: Sener EF, Canatan H, Ozkul Y

Abstract
Autism spectrum disorders (ASD) is characterized by three core symptoms with impaired reciprocal social interaction and communication, a pattern of repetitive behavior and/or restricted interests in early childhood. The prevalence is higher in male children than in female children. As a complex neurodevelopmental disorder, the phenotype and severity of autism are extremely heterogeneous with differences from one patient to another. Genetics has a key role in the etiology of autism. Environmental factors are also interacting with the genetic profile and cause abnormal changes in neuronal development, brain growth, and functional connectivity. The term of exome represents less than 1% of the human genome, but contains 85% of known disease-causing variants. Whole-exome sequencing (WES) is an application of the next generation sequencing technology to determine the variations of all coding regions, or exons of known genes. For this reason, WES has been extensively used for clinical studies in the recent years. WES has achieved great success in the past years for identifying Mendelian disease genes. This review evaluates the potential of current findings in ASD for application in next generation sequencing technology, particularly WES. WES and whole-genome sequencing (WGS) approaches may lead to the discovery of underlying genetic factors for ASD and may thereby identify novel therapeutic targets for this disorder.

PMID: 27247591 [PubMed]

An ontology for Autism Spectrum Disorder (ASD) to infer ASD phenotypes from Autism Diagnostic Interview-Revised data.

June 2, 2016 - 8:19am
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An ontology for Autism Spectrum Disorder (ASD) to infer ASD phenotypes from Autism Diagnostic Interview-Revised data.

J Biomed Inform. 2015 Aug;56:333-47

Authors: Mugzach O, Peleg M, Bagley SC, Guter SJ, Cook EH, Altman RB

Abstract
OBJECTIVE: Our goal is to create an ontology that will allow data integration and reasoning with subject data to classify subjects, and based on this classification, to infer new knowledge on Autism Spectrum Disorder (ASD) and related neurodevelopmental disorders (NDD). We take a first step toward this goal by extending an existing autism ontology to allow automatic inference of ASD phenotypes and Diagnostic & Statistical Manual of Mental Disorders (DSM) criteria based on subjects' Autism Diagnostic Interview-Revised (ADI-R) assessment data.
MATERIALS AND METHODS: Knowledge regarding diagnostic instruments, ASD phenotypes and risk factors was added to augment an existing autism ontology via Ontology Web Language class definitions and semantic web rules. We developed a custom Protégé plugin for enumerating combinatorial OWL axioms to support the many-to-many relations of ADI-R items to diagnostic categories in the DSM. We utilized a reasoner to infer whether 2642 subjects, whose data was obtained from the Simons Foundation Autism Research Initiative, meet DSM-IV-TR (DSM-IV) and DSM-5 diagnostic criteria based on their ADI-R data.
RESULTS: We extended the ontology by adding 443 classes and 632 rules that represent phenotypes, along with their synonyms, environmental risk factors, and frequency of comorbidities. Applying the rules on the data set showed that the method produced accurate results: the true positive and true negative rates for inferring autistic disorder diagnosis according to DSM-IV criteria were 1 and 0.065, respectively; the true positive rate for inferring ASD based on DSM-5 criteria was 0.94.
DISCUSSION: The ontology allows automatic inference of subjects' disease phenotypes and diagnosis with high accuracy.
CONCLUSION: The ontology may benefit future studies by serving as a knowledge base for ASD. In addition, by adding knowledge of related NDDs, commonalities and differences in manifestations and risk factors could be automatically inferred, contributing to the understanding of ASD pathophysiology.

PMID: 26151311 [PubMed - indexed for MEDLINE]

T-Brain-1--A Potential Master Regulator in Autism Spectrum Disorders.

June 2, 2016 - 8:19am
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T-Brain-1--A Potential Master Regulator in Autism Spectrum Disorders.

Autism Res. 2015 Aug;8(4):412-26

Authors: Chuang HC, Huang TN, Hsueh YP

Abstract
T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor. It is therefore possible that TBR1 controls the expression of other autism risk factors. The downstream genes of TBR1 have been identified using microarray and promoter analyses. In this study, we annotated individual genes downstream of TBR1 and investigated any associations with ASDs through extensive literature searches. Of 124 TBR1 target genes, 23 were reported to be associated with ASDs. In addition, one gene, Kiaa0319, is a known causative gene for dyslexia, a disorder frequently associated with autism. A change in expression level in 10 of these 24 genes has been previously confirmed. We further validated the alteration of RNA expression levels of Kiaa0319, Baiap2, and Gad1 in Tbr1 deficient mice. Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis. A further five of the 24 genes (Cd44, Cdh8, Cntn6, Gpc6, and Ntng1) encode membrane proteins that regulate cell adhesion and axonal outgrowth. These genes likely contribute to the role of TBR1 in regulation of neuronal migration and axonal extension. Besides, decreases in Grin2b expression and increases in Gad1 expression imply that neuronal activity may be aberrant in Tbr1 deficient mice. These analyses provide direction for future experiments to reveal the pathogenic mechanism of autism.

PMID: 25600067 [PubMed - indexed for MEDLINE]

Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.

June 2, 2016 - 8:19am
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Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.

Mol Syst Biol. 2014;10:774

Authors: Li J, Shi M, Ma Z, Zhao S, Euskirchen G, Ziskin J, Urban A, Hallmayer J, Snyder M

Abstract
Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center. RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology.

PMID: 25549968 [PubMed - indexed for MEDLINE]

AMPD1 functional variants associated with autism in Han Chinese population.

June 2, 2016 - 8:19am
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AMPD1 functional variants associated with autism in Han Chinese population.

Eur Arch Psychiatry Clin Neurosci. 2015 Sep;265(6):511-7

Authors: Zhang L, Ou J, Xu X, Peng Y, Guo H, Pan Y, Chen J, Wang T, Peng H, Liu Q, Tian D, Pan Q, Zou X, Zhao J, Hu Z, Xia K

Abstract
Autism is a childhood neurodevelopmental disorder with high heterogeneity. Following our genome-wide associated loci with autism, we performed sequencing analysis of the coding regions, UTR and flanking splice junctions of AMPD1 in 830 Chinese autism individuals as well as 514 unrelated normal controls. Fourteen novel variants in the coding sequence were identified, including 11 missense variants and 3 synonymous mutations. Among these missense variants, 10 variants were absent in 514 control subjects, and conservative and functional prediction was carried out. Mitochondria activity and lactate dehydrogenase assay were performed in 5 patients' lymphoblast cell lines; p.P572S and p.S626C showed decreased mitochondrial complex I activity, and p.S626C increased lactate dehydrogenase release in medium. Conclusively, our data suggested that mutational variants in AMPD1 contribute to autism risk in Han Chinese population, uncovering the contribution of mutant protein to disease development that operates via mitochondria dysfunction and cell necrosis.

PMID: 25155876 [PubMed - indexed for MEDLINE]

Modeling psychiatric disorders: from genomic findings to cellular phenotypes.

June 1, 2016 - 11:10am

Modeling psychiatric disorders: from genomic findings to cellular phenotypes.

Mol Psychiatry. 2016 May 31;

Authors: Falk A, Heine VM, Harwood AJ, Sullivan PF, Peitz M, Brüstle O, Shen S, Sun YM, Glover JC, Posthuma D, Djurovic S

Abstract
Major programs in psychiatric genetics have identified >150 risk loci for psychiatric disorders. These loci converge on a small number of functional pathways, which span conventional diagnostic criteria, suggesting a partly common biology underlying schizophrenia, autism and other psychiatric disorders. Nevertheless, the cellular phenotypes that capture the fundamental features of psychiatric disorders have not yet been determined. Recent advances in genetics and stem cell biology offer new prospects for cell-based modeling of psychiatric disorders. The advent of cell reprogramming and induced pluripotent stem cells (iPSC) provides an opportunity to translate genetic findings into patient-specific in vitro models. iPSC technology is less than a decade old but holds great promise for bridging the gaps between patients, genetics and biology. Despite many obvious advantages, iPSC studies still present multiple challenges. In this expert review, we critically review the challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes.Molecular Psychiatry advance online publication, 31 May 2016; doi:10.1038/mp.2016.89.

PMID: 27240529 [PubMed - as supplied by publisher]

Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin.

June 1, 2016 - 11:10am
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Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin.

Cell. 2016 Jan 14;164(1-2):183-96

Authors: Singh SK, Stogsdill JA, Pulimood NS, Dingsdale H, Kim YH, Pilaz LJ, Kim IH, Manhaes AC, Rodrigues WS, Pamukcu A, Enustun E, Ertuz Z, Scheiffele P, Soderling SH, Silver DL, Ji RR, Medina AE, Eroglu C

Abstract
Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism.

PMID: 26771491 [PubMed - indexed for MEDLINE]

The 15q13.3 deletion syndrome: Deficient α(7)-containing nicotinic acetylcholine receptor-mediated neurotransmission in the pathogenesis of neurodevelopmental disorders.

June 1, 2016 - 11:10am
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The 15q13.3 deletion syndrome: Deficient α(7)-containing nicotinic acetylcholine receptor-mediated neurotransmission in the pathogenesis of neurodevelopmental disorders.

Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jan 4;64:109-17

Authors: Deutsch SI, Burket JA, Benson AD, Urbano MR

Abstract
Array comparative genomic hybridization (array CGH) has led to the identification of microdeletions of the proximal region of chromosome 15q between breakpoints (BP) 3 or BP4 and BP5 encompassing CHRNA7, the gene encoding the α7-nicotinic acetylcholine receptor (α7nAChR) subunit. Phenotypic manifestations of persons with these microdeletions are variable and some heterozygous carriers are seemingly unaffected, consistent with their variable expressivity and incomplete penetrance. Nonetheless, the 15q13.3 deletion syndrome is associated with several neuropsychiatric disorders, including idiopathic generalized epilepsy, intellectual disability, autism spectrum disorders (ASDs) and schizophrenia. Haploinsufficient expression of CHRNA7 in this syndrome has highlighted important roles the α7nAChR plays in the developing brain and normal processes of attention, cognition, memory and behavior throughout life. Importantly, the existence of the 15q13.3 deletion syndrome contributes to an emerging literature supporting clinical trials therapeutically targeting the α7nAChR in disorders such as ASDs and schizophrenia, including the larger population of patients with no evidence of haploinsufficient expression of CHRNA7. Translational clinical trials will be facilitated by the existence of positive allosteric modulators (PAMs) of the α7nAChR that act at sites on the receptor distinct from the orthosteric site that binds acetylcholine and choline, the receptor's endogenous ligands. PAMs lack intrinsic efficacy by themselves, but act where and when the endogenous ligands are released in response to relevant social and cognitive provocations to increase the likelihood they will result in α7nAChR ion channel activation.

PMID: 26257138 [PubMed - indexed for MEDLINE]

Perception of emotion in facial stimuli: The interaction of ADRA2A and COMT genotypes, and sex.

June 1, 2016 - 11:10am
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Perception of emotion in facial stimuli: The interaction of ADRA2A and COMT genotypes, and sex.

Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jan 4;64:87-95

Authors: Tamm G, Kreegipuu K, Harro J

Abstract
Emotional facial stimuli are important social signals that are essential to be perceived and recognized in order to make appropriate decisions and responses in everyday communication. The ability to voluntarily guide attention to perceive and recognize emotions, and react to them varies largely across individuals, and has a strong genetic component (Friedman et al., 2008). Two key genetic variants of the catecholamine system that have been related to emotion perception and attention are the catechol-O-methyl transferase genetic variant (COMT Val158Met) and the α2A-receptor gene promoter polymorphism (ADRA2A C-1291G) accordingly. So far, the interaction of the two with sex in emotion perception has not been studied. Multilevel modeling method was applied to study how COMT Val158Met, ADRA2A C-1291G and sex are associated with measures of emotion perception in a large sample of young adults. Participants (n=506) completed emotion recognition and behavioral emotion detection tasks. It was found that COMT Val158Met genotype in combination with the ADRA2A C-1291G and sex predicts emotion detection, and perception of valence and arousal. In simple visual detection, the ADRA2A C-1291G G-allele leads to slower detection of a highly arousing face (scheming), which is modulated by each additional COMT Val158Met Met-allele and male sex predicting faster responses. The combination of G-allele, Met-allele and male sex also predicts higher perceived negativity in sad faces. No effects of C-1291G, Val158Met, and sex were found on verbal emotion recognition. Applying the findings to study the interplay between catecholamine-O-methyl transferase activity and α2A-receptors in emotion perception disorders (such as ADHD, autism and schizophrenia) in men and women would be the next step towards understanding individual differences in emotion perception.

PMID: 26234518 [PubMed - indexed for MEDLINE]

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