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Human pluripotent stem cell models of autism spectrum disorder: emerging frontiers, opportunities, and challenges towards neuronal networks in a dish.

November 13, 2014 - 3:31pm
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Human pluripotent stem cell models of autism spectrum disorder: emerging frontiers, opportunities, and challenges towards neuronal networks in a dish.

Psychopharmacology (Berl). 2014 Mar;231(6):1089-104

Authors: Aigner S, Heckel T, Zhang JD, Andreae LC, Jagasia R

Abstract
Autism spectrum disorder (ASD) is characterized by deficits in language development and social cognition and the manifestation of repetitive and restrictive behaviors. Despite recent major advances, our understanding of the pathophysiological mechanisms leading to ASD is limited. Although most ASD cases have unknown genetic underpinnings, animal and human cellular models of several rare, genetically defined syndromic forms of ASD have provided evidence for shared pathophysiological mechanisms that may extend to idiopathic cases. Here, we review our current knowledge of the genetic basis and molecular etiology of ASD and highlight how human pluripotent stem cell-based disease models have the potential to advance our understanding of molecular dysfunction. We summarize landmark studies in which neuronal cell populations generated from human embryonic stem cells and patient-derived induced pluripotent stem cells have served to model disease mechanisms, and we discuss recent technological advances that may ultimately allow in vitro modeling of specific human neuronal circuitry dysfunction in ASD. We propose that these advances now offer an unprecedented opportunity to help better understand ASD pathophysiology. This should ultimately enable the development of cellular models for ASD, allowing drug screening and the identification of molecular biomarkers for patient stratification.

PMID: 24232378 [PubMed - indexed for MEDLINE]

The challenges of clinical trials in fragile X syndrome.

November 13, 2014 - 3:31pm
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The challenges of clinical trials in fragile X syndrome.

Psychopharmacology (Berl). 2014 Mar;231(6):1237-50

Authors: Jacquemont S, Berry-Kravis E, Hagerman R, von Raison F, Gasparini F, Apostol G, Ufer M, Des Portes V, Gomez-Mancilla B

Abstract
RATIONALE: Advances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement.
OBJECTIVES: We review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders.
RESULTS: Residual levels of fragile X mental retardation protein (FMRP) expression explain in part the heterogeneity in the FXS phenotype; studies indicate a correlation with both cognitive and behavioral deficits. However, this does not fully explain the extent of phenotypic variance observed or the variability of drug response. Post hoc analyses of studies involving the selective mGluR5 antagonist mavoglurant and the GABAB agonist arbaclofen have uncovered significant therapeutic responses following patient stratification according to FMR1 promoter methylation patterns or baseline severity of social withdrawal, respectively. Future studies designed to quantify disease modification will need to develop new strategies to track changes effectively over time and in multiple symptom domains.
CONCLUSION: Appropriate selection of patients and outcome measures is central to optimizing future clinical investigations of these complex disorders.

PMID: 24173622 [PubMed - indexed for MEDLINE]

The utility of patient specific induced pluripotent stem cells for the modelling of Autistic Spectrum Disorders.

November 13, 2014 - 3:31pm
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The utility of patient specific induced pluripotent stem cells for the modelling of Autistic Spectrum Disorders.

Psychopharmacology (Berl). 2014 Mar;231(6):1079-88

Authors: Cocks G, Curran S, Gami P, Uwanogho D, Jeffries AR, Kathuria A, Lucchesi W, Wood V, Dixon R, Ogilvie C, Steckler T, Price J

Abstract
Until now, models of psychiatric diseases have typically been animal models. Whether they were to be used to further understand the pathophysiology of the disorder, or as drug discovery tools, animal models have been the choice of preference in mimicking psychiatric disorders in an experimental setting. While there have been cellular models, they have generally been lacking in validity. This situation is changing with the advent of patient-specific induced pluripotent stem cells (iPSCs). In this article, we give a methodological evaluation of the current state of the iPS technology with reference to our own work in generating patient-specific iPSCs for the study of autistic spectrum disorder (ASD). In addition, we will give a broader perspective on the validity of this technology and to what extent it can be expected to complement animal models of ASD in the coming years.

PMID: 23839283 [PubMed - indexed for MEDLINE]

Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant.

November 13, 2014 - 3:31pm
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Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant.

Psychopharmacology (Berl). 2014 Mar;231(6):1227-35

Authors: Pop AS, Levenga J, de Esch CE, Buijsen RA, Nieuwenhuizen IM, Li T, Isaacs A, Gasparini F, Oostra BA, Willemsen R

Abstract
Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and autism. The disease is a result of lack of expression of the fragile X mental retardation protein. Brain tissues of patients with FXS and mice with FMRP deficiency have shown an abnormal dendritic spine phenotype. We investigated the dendritic spine length and density of hippocampal CA1 pyramidal neurons in 2-, 10-, and 25-week-old Fmr1 knockout (KO). Next, we studied the effects of long-term treatment with an mGluR5 antagonist, AFQ056/Mavoglurant, on the spine phenotype in adult Fmr1 KO mice. We observed alterations in the spine phenotype during development, with a decreased spine length in 2-week-old Fmr1 KO mice compared with age-match wild-type littermates, but with increased spine length in Fmr1 KO mice compared with 10- and 25-week-old wild-type controls. No difference was found in spine density at any age. We report a rescue of the abnormal spine length in adult Fmr1 KO mice after a long-term treatment with AFQ056/Mavoglurant. This finding suggests that long-term treatment at later stage is sufficient to reverse the structural spine abnormalities and represents a starting point for future studies aimed at improving treatments for FXS.

PMID: 23254376 [PubMed - indexed for MEDLINE]

Cell-type-specific repression by methyl-CpG-binding protein 2 is biased toward long genes.

November 12, 2014 - 8:56am
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Cell-type-specific repression by methyl-CpG-binding protein 2 is biased toward long genes.

J Neurosci. 2014 Sep 17;34(38):12877-83

Authors: Sugino K, Hempel CM, Okaty BW, Arnson HA, Kato S, Dani VS, Nelson SB

Abstract
Mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome and related autism spectrum disorders (Amir et al., 1999). MeCP2 is believed to be required for proper regulation of brain gene expression, but prior microarray studies in Mecp2 knock-out mice using brain tissue homogenates have revealed only subtle changes in gene expression (Tudor et al., 2002; Nuber et al., 2005; Jordan et al., 2007; Chahrour et al., 2008). Here, by profiling discrete subtypes of neurons we uncovered more dramatic effects of MeCP2 on gene expression, overcoming the "dilution problem" associated with assaying homogenates of complex tissues. The results reveal misregulation of genes involved in neuronal connectivity and communication. Importantly, genes upregulated following loss of MeCP2 are biased toward longer genes but this is not true for downregulated genes, suggesting MeCP2 may selectively repress long genes. Because genes involved in neuronal connectivity and communication, such as cell adhesion and cell-cell signaling genes, are enriched among longer genes, their misregulation following loss of MeCP2 suggests a possible etiology for altered circuit function in Rett syndrome.

PMID: 25232122 [PubMed - indexed for MEDLINE]

Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice.

November 11, 2014 - 8:41am

Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice.

Nat Neurosci. 2014 Nov 10;

Authors: Zhang Y, Bonnan A, Bony G, Ferezou I, Pietropaolo S, Ginger M, Sans N, Rossier J, Oostra B, LeMasson G, Frick A

Abstract
Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders, but little is known about the dendritic mechanisms underlying these phenomena. We found that the primary somatosensory neocortex (S1) was hyperexcited in response to tactile sensory stimulation in Fmr1(-/y) mice. This correlated with neuronal and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major aspects of neuronal computation, from the integration of synaptic input to the generation of action potential output. Using dendritic electrophysiological recordings, calcium imaging, pharmacology, biochemistry and a computer model, we found that this defect was, at least in part, attributable to the reduction and dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BKCa channels. Our results provide strong evidence pointing to the utility of BKCa channel openers for the treatment of the sensory hypersensitivity aspects of FXS.

PMID: 25383903 [PubMed - as supplied by publisher]

Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population.

November 11, 2014 - 8:41am
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Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population.

J Zhejiang Univ Sci B. 2014 Mar;15(3):264-71

Authors: Liang S, Wang XL, Zou MY, Wang H, Zhou X, Sun CH, Xia W, Wu LJ, Fujisawa TX, Tomoda A

Abstract
OBJECTIVE: A study in a Caucasian population has identified two single-nucleotide polymorphisms (SNPs) in ZNF533, one in DOCK4, and two in IMMP2L, which were all significantly associated with autism. They are located in AUTS1 and AUTS5, which have been identified as autism susceptibility loci in several genome-wide screens. The present study aimed to investigate whether ZNF533, DOCK4, and IMMP2L genes are also associated with autism in a northeastern Chinese Han population.
METHODS: We performed a similar association study using families with three individuals (one autistic child and two unaffected parents). A family-based transmission disequilibrium test (TDT) was used to analyze the results.
RESULTS: There were significant associations between autism and the two SNPs of ZNF533 gene (rs11885327: χ(2)=4.5200, P=0.0335; rs1964081: χ(2)=4.2610, P=0.0390) and the SNP of DOCK4 gene (rs2217262: χ(2)=5.3430, P=0.0208).
CONCLUSIONS: Our data suggest that ZNF533 and DOCK4 genes are linked to a predisposition to autism in the northeastern Chinese Han population.

PMID: 24599690 [PubMed - indexed for MEDLINE]

A Rare Duplication on Chromosome 16p11.2 Is Identified in Patients with Psychosis in Alzheimer's Disease.

November 8, 2014 - 7:44am

A Rare Duplication on Chromosome 16p11.2 Is Identified in Patients with Psychosis in Alzheimer's Disease.

PLoS One. 2014;9(11):e111462

Authors: Zheng X, Demirci FY, Barmada MM, Richardson GA, Lopez OL, Sweet RA, Kamboh MI, Feingold E

Abstract
Epidemiological and genetic studies suggest that schizophrenia and autism may share genetic links. Besides common single nucleotide polymorphisms, recent data suggest that some rare copy number variants (CNVs) are risk factors for both disorders. Because we have previously found that schizophrenia and psychosis in Alzheimer's disease (AD+P) share some genetic risk, we investigated whether CNVs reported in schizophrenia and autism are also linked to AD+P. We searched for CNVs associated with AD+P in 7 recurrent CNV regions that have been previously identified across autism and schizophrenia, using the Illumina HumanOmni1-Quad BeadChip. A chromosome 16p11.2 duplication CNV (chr16: 29,554,843-30,105,652) was identified in 2 of 440 AD+P subjects, but not in 136 AD subjects without psychosis, or in 593 AD subjects with intermediate psychosis status, or in 855 non-AD individuals. The frequency of this duplication CNV in AD+P (0.46%) was similar to that reported previously in schizophrenia (0.46%). This duplication CNV was further validated using the NanoString nCounter CNV Custom CodeSets. The 16p11.2 duplication has been associated with developmental delay, intellectual disability, behavioral problems, autism, schizophrenia (SCZ), and bipolar disorder. These two AD+P patients had no personal of, nor any identified family history of, SCZ, bipolar disorder and autism. To the best of our knowledge, our case report is the first suggestion that 16p11.2 duplication is also linked to AD+P. Although rare, this CNV may have an important role in the development of psychosis.

PMID: 25379732 [PubMed - as supplied by publisher]

Chronic desipramine treatment rescues depression-related, social and cognitive deficits in Engrailed-2 knockout mice.

November 8, 2014 - 7:44am
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Chronic desipramine treatment rescues depression-related, social and cognitive deficits in Engrailed-2 knockout mice.

Genes Brain Behav. 2014 Mar;13(3):286-298

Authors: Brielmaier J, Senerth JM, Silverman JL, Matteson PG, Millonig JH, DiCicco-Bloom E, Crawley JN

Abstract
Engrailed-2 (En2) is a homeobox transcription factor that regulates neurodevelopmental processes including neuronal connectivity and elaboration of monoaminergic neurons in the ventral hindbrain. We previously reported abnormalities in brain noradrenergic concentrations in En2 null mutant mice that were accompanied by increased immobility in the forced swim test, relevant to depression. An EN2 genetic polymorphism has been associated with autism spectrum disorders, and mice with a deletion in En2 display social abnormalities and cognitive deficits that may be relevant to multiple neuropsychiatric conditions. This study evaluated the ability of chronic treatment with desipramine (DMI), a selective norepinephrine (NE) reuptake inhibitor and classical antidepressant, to reverse behavioral abnormalities in En2−/− mice. Desipramine treatment significantly reduced immobility in the tail suspension and forced swim tests, restored sociability in the three-chambered social approach task and reversed impairments in contextual fear conditioning in En2−/− mice. Our findings indicate that modulation of brain noradrenergic systems rescues the depression-related phenotype in En2−/− mice and suggest new roles for NE in the pathophysiology of the social and cognitive deficits seen in neuropsychiatric disorders such as autism or schizophrenia.

PMID: 24730055 [PubMed - indexed for MEDLINE]

Characterisation of genetic variation in ST8SIA2 and its interaction region in NCAM1 in patients with bipolar disorder.

November 8, 2014 - 7:44am
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Characterisation of genetic variation in ST8SIA2 and its interaction region in NCAM1 in patients with bipolar disorder.

PLoS One. 2014;9(3):e92556

Authors: Shaw AD, Tiwari Y, Kaplan W, Heath A, Mitchell PB, Schofield PR, Fullerton JM

Abstract
Alpha-2,8-sialyltransferase 2 (ST8SIA2) is an enzyme responsible for the transfer of polysialic acid (PSA) to glycoproteins, principally the neuronal cell adhesion molecule (NCAM1), and is involved in neuronal plasticity. Variants within ST8SIA2 have previously shown association with bipolar disorder, schizophrenia and autism. In addition, altered PSA-NCAM expression in brains of patients with schizophrenia or bipolar disorder indicates a functional dysregulation of glycosylation in mental illness. To explore the role of sequence variation affecting PSA-NCAM formation, we conducted a targeted re-sequencing study of a ∼ 100 kb region--including the entire ST8SIA2 gene and its region of interaction with NCAM1--in 48 Caucasian cases with bipolar disorder using the Roche 454 platform. We identified over 400 DNA variants, including 47 putative novel variants not described in dbSNP. Validation of a subset of variants via Sequenom showed high reliability of Roche 454 genotype calls (97% genotype concordance, with 80% of novel variants independently verified). We did not observe major loss-of-function mutations that would affect PSA-NCAM formation, either by ablating ST8SIA2 function or by affecting the ability of NCAM1 to be glycosylated. However, we identified 13 SNPs in the UTRs of ST8SIA2, a synonymous coding SNP in exon 5 (rs2305561, P207P) and many additional non-coding variants that may influence splicing or regulation of ST8SIA2 expression. We calculated nucleotide diversity within ST8SIA2 on specific haplotypes, finding that the diversity on the specific "risk" and "protective" haplotypes was lower than other non-disease-associated haplotypes, suggesting that putative functional variation may have arisen on a spectrum of haplotypes. We have identified common and novel variants (rs11074064, rs722645, 15:92961050) that exist on a spectrum of haplotypes, yet are plausible candidates for conferring the effect of risk and protective haplotypes via multiple enhancer elements. A Galaxy workflow/pipeline for sequence analysis used herein is available at: https://main.g2.bx.psu.edu/u/a-shaw-neura/p/next-generation-resources.

PMID: 24651862 [PubMed - indexed for MEDLINE]

Quantitative trait loci mapping and gene network analysis implicate protocadherin-15 as a determinant of brain serotonin transporter expression.

November 8, 2014 - 7:44am
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Quantitative trait loci mapping and gene network analysis implicate protocadherin-15 as a determinant of brain serotonin transporter expression.

Genes Brain Behav. 2014 Mar;13(3):261-75

Authors: Ye R, Carneiro AM, Han Q, Airey D, Sanders-Bush E, Zhang B, Lu L, Williams R, Blakely RD

Abstract
Presynaptic serotonin (5-hydroxytryptamine, 5-HT) transporters (SERT) regulate 5-HT signaling via antidepressant-sensitive clearance of released neurotransmitter. Polymorphisms in the human SERT gene (SLC6A4) have been linked to risk for multiple neuropsychiatric disorders, including depression, obsessive-compulsive disorder and autism. Using BXD recombinant inbred mice, a genetic reference population that can support the discovery of novel determinants of complex traits, merging collective trait assessments with bioinformatics approaches, we examine phenotypic and molecular networks associated with SERT gene and protein expression. Correlational analyses revealed a network of genes that significantly associated with SERT mRNA levels. We quantified SERT protein expression levels and identified region- and gender-specific quantitative trait loci (QTLs), one of which associated with male midbrain SERT protein expression, centered on the protocadherin-15 gene (Pcdh15), overlapped with a QTL for midbrain 5-HT levels. Pcdh15 was also the only QTL-associated gene whose midbrain mRNA expression significantly associated with both SERT protein and 5-HT traits, suggesting an unrecognized role of the cell adhesion protein in the development or function of 5-HT neurons. To test this hypothesis, we assessed SERT protein and 5-HT traits in the Pcdh15 functional null line (Pcdh15(av-) (3J) ), studies that revealed a strong, negative influence of Pcdh15 on these phenotypes. Together, our findings illustrate the power of multidimensional profiling of recombinant inbred lines in the analysis of molecular networks that support synaptic signaling, and that, as in the case of Pcdh15, can reveal novel relationships that may underlie risk for mental illness.

PMID: 24405699 [PubMed - indexed for MEDLINE]

Genetically meaningful phenotypic subgroups in autism spectrum disorders.

November 8, 2014 - 7:44am
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Genetically meaningful phenotypic subgroups in autism spectrum disorders.

Genes Brain Behav. 2014 Mar;13(3):276-85

Authors: Veatch OJ, Veenstra-Vanderweele J, Potter M, Pericak-Vance MA, Haines JL

Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with strong evidence for genetic susceptibility. However, the effect sizes for implicated chromosomal loci are small, hard to replicate and current evidence does not explain the majority of the estimated heritability. Phenotypic heterogeneity could be one phenomenon complicating identification of genetic factors. We used data from the Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, Vineland Adaptive Behavior Scales, head circumferences, and ages at exams as classifying variables to identify more clinically similar subgroups of individuals with ASD. We identified two distinct subgroups of cases within the Autism Genetic Resource Exchange dataset, primarily defined by the overall severity of evaluated traits. In addition, there was significant familial clustering within subgroups (odds ratio, OR ≈ 1.38-1.42, P < 0.00001), and genotypes were more similar within subgroups compared to the unsubgrouped dataset (Fst = 0.17 ± 0.0.0009). These results suggest that the subgroups recapitulate genetic etiology. Using the same approach in an independent dataset from the Autism Genome Project, we similarly identified two distinct subgroups of cases and confirmed this severity-based dichotomy. We also observed evidence for genetic contributions to subgroups identified in the replication dataset. Our results provide more effective methods of phenotype definition that should increase power to detect genetic factors influencing risk for ASD.

PMID: 24373520 [PubMed - indexed for MEDLINE]

Transition to adult life in the monogenic epilepsies.

November 7, 2014 - 7:26am
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Transition to adult life in the monogenic epilepsies.

Epilepsia. 2014 Aug;55 Suppl 3:12-5

Authors: Scheffer IE, Dravet C

Abstract
There are many monogenic disorders associated with epilepsy that begin in childhood and persist into adult life. Each of these disorders raises specific issues for transition, in addition to common issues facing this group of patients as they move from pediatric to adult care. Such comorbidities include psychiatric and movement disorders. Epileptic encephalopathies may be caused by monogenic disorders, with Dravet syndrome being the best characterized. Although some patients have a relatively good adult outcome, others have persisting severe epilepsy complicated by autistic spectrum disorder and problems with gait. When reevaluating a patient as they transition to adult care, a thorough reconsideration of the genetic etiology of their epilepsy should be performed. This should be followed by genetic counseling for the patient and their family members.

PMID: 25209079 [PubMed - indexed for MEDLINE]

Alterations in the cholinergic system of brain stem neurons in a mouse model of Rett syndrome.

November 7, 2014 - 7:26am
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Alterations in the cholinergic system of brain stem neurons in a mouse model of Rett syndrome.

Am J Physiol Cell Physiol. 2014 Sep 15;307(6):C508-20

Authors: Oginsky MF, Cui N, Zhong W, Johnson CM, Jiang C

Abstract
Rett syndrome is an autism-spectrum disorder resulting from mutations to the X-linked gene, methyl-CpG binding protein 2 (MeCP2), which causes abnormalities in many systems. It is possible that the body may develop certain compensatory mechanisms to alleviate the abnormalities. The norepinephrine system originating mainly in the locus coeruleus (LC) is defective in Rett syndrome and Mecp2-null mice. LC neurons are subject to modulation by GABA, glutamate, and acetylcholine (ACh), providing an ideal system to test the compensatory hypothesis. Here we show evidence for potential compensatory modulation of LC neurons by post- and presynaptic ACh inputs. We found that the postsynaptic currents of nicotinic ACh receptors (nAChR) were smaller in amplitude and longer in decay time in the Mecp2-null mice than in the wild type. Single-cell PCR analysis showed a decrease in the expression of α3-, α4-, α7-, and β3-subunits and an increase in the α5- and α6-subunits in the mutant mice. The α5-subunit was present in many of the LC neurons with slow-decay nAChR currents. The nicotinic modulation of spontaneous GABAA-ergic inhibitory postsynaptic currents in LC neurons was enhanced in Mecp2-null mice. In contrast, the nAChR manipulation of glutamatergic input to LC neurons was unaffected in both groups of mice. Our current-clamp studies showed that the modulation of LC neurons by ACh input was reduced moderately in Mecp2-null mice, despite the major decrease in nAChR currents, suggesting possible compensatory processes may take place, thus reducing the defects to a lesser extent in LC neurons.

PMID: 25009110 [PubMed - indexed for MEDLINE]

STRIPAK complexes: structure, biological function, and involvement in human diseases.

November 7, 2014 - 7:26am
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STRIPAK complexes: structure, biological function, and involvement in human diseases.

Int J Biochem Cell Biol. 2014 Feb;47:118-48

Authors: Hwang J, Pallas DC

Abstract
The mammalian striatin family consists of three proteins, striatin, S/G2 nuclear autoantigen, and zinedin. Striatin family members have no intrinsic catalytic activity, but rather function as scaffolding proteins. Remarkably, they organize multiple diverse, large signaling complexes that participate in a variety of cellular processes. Moreover, they appear to be regulatory/targeting subunits for the major eukaryotic serine/threonine protein phosphatase 2A. In addition, striatin family members associate with germinal center kinase III kinases as well as other novel components, earning these assemblies the name striatin-interacting phosphatase and kinase (STRIPAK) complexes. Recently, there has been a great increase in functional and mechanistic studies aimed at identifying and understanding the roles of STRIPAK and STRIPAK-like complexes in cellular processes of multiple organisms. These studies have identified novel STRIPAK and STRIPAK-like complexes and have explored their roles in specific signaling pathways. Together, the results of these studies have sparked increased interest in striatin family complexes because they have revealed roles in signaling, cell cycle control, apoptosis, vesicular trafficking, Golgi assembly, cell polarity, cell migration, neural and vascular development, and cardiac function. Moreover, STRIPAK complexes have been connected to clinical conditions, including cardiac disease, diabetes, autism, and cerebral cavernous malformation. In this review, we discuss the expression, localization, and protein domain structure of striatin family members. Then we consider the diverse complexes these proteins and their homologs form in various organisms, emphasizing what is known regarding function and regulation. Finally, we explore possible roles of striatin family complexes in disease, especially cerebral cavernous malformation.

PMID: 24333164 [PubMed - indexed for MEDLINE]

No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia.

November 6, 2014 - 7:13am

No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia.

Eur J Hum Genet. 2014 Nov 5;

Authors: Ruderfer DM, Lim ET, Genovese G, Moran JL, Hultman CM, Sullivan PF, McCarroll SA, Holmans P, Sklar P, Purcell SM

Abstract
Recessive inheritance of gene disrupting alleles, either through homozygosity at a specific site or compound heterozygosity, have been demonstrated to underlie many Mendelian diseases and some complex psychiatric disorders. On the basis of exome sequencing data, an increased burden of complete knockout (homozygous or compound heterozygous) variants has been identified in autism. In addition, using single-nucleotide polymorphism microarray data, an increased rate of homozygosity by descent, or autozygosity, has been linked to the risk of schizophrenia (SCZ). Here, in a large Swedish case-control SCZ sample (11 244 individuals, 5079 of whom have exome sequence data available), we survey the contribution of both autozygosity and complete knockouts to disease risk. We do not find evidence for association with SCZ, either genome wide or at specific loci. However, we note the possible impact of sample size and population genetic factors on the power to detect and quantify any burden that may exist.European Journal of Human Genetics advance online publication, 5 November 2014; doi:10.1038/ejhg.2014.228.

PMID: 25370044 [PubMed - as supplied by publisher]

Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy.

November 5, 2014 - 7:08am
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Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy.

Am J Med Genet A. 2014 Mar;164A(3):782-8

Authors: Kamien B, Harraway J, Lundie B, Smallhorne L, Gibbs V, Heath A, Fullerton JM

Abstract
We present a patient with a behavioral disorder, epilepsy, and autism spectrum disorder who has a 520 kb chromosomal deletion at 15q26.1 encompassing three genes: ST8SIA2, C15orf32, and FAM174B. Alpha-2,8-Sialyltransferase 2 (ST8SIA2) is expressed in the developing brain and appears to play an important role in neuronal migration, axon guidance and synaptic plasticity. It has recently been implicated in a genome wide association study as a potential factor underlying autism, and has also been implicated in the pathogenesis of bipolar disorder and schizophrenia. This case provides supportive evidence that ST8SIA2 haploinsufficiency may play a role in neurobehavioral phenotypes.

PMID: 24357335 [PubMed - indexed for MEDLINE]

Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome down to 1.6 Mb including PAX6, WT1, and PRRG4.

November 5, 2014 - 7:08am
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Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome down to 1.6 Mb including PAX6, WT1, and PRRG4.

Am J Med Genet A. 2014 Mar;164A(3):634-8

Authors: Yamamoto T, Togawa M, Shimada S, Sangu N, Shimojima K, Okamoto N

Abstract
Interstitial deletions of the 11p13 region are known to cause WAGR (Wilms tumor, aniridia, genitourinary malformation, and "mental retardation") syndrome, a contiguous gene deletion syndrome due to haploinsufficiencies of the genes in this region, including WT1 and PAX6. Developmental delay and autistic features are major complications of this syndrome. Previously, some genes located in this region have been suggested as responsible for autistic features. In this study, we identified two patients who showed the chromosomal deletions involving 11p13. Patient 1, having an 8.6 Mb deletion of chr11p14.1p12:29,676,434-38,237,948, exhibited a phenotype typical of WAGR syndrome and had severe developmental delay and autistic behaviors. On the other hand, Patient 2 had a larger aberration region in 11p14.1-p12 which was split into two regions, that is, a 2.2-Mb region of chr11p14.1: 29,195,161-31,349,732 and a 10.5-Mb region of chr11p13p12: 32,990,627-43,492,580. As a consequence, 1.6 Mb region of the WAGR syndrome critical region was intact between the two deletions. This patient showed no symptom of WAGR syndrome and no autistic behaviors. Therefore, the region responsible for severe developmental delay and autistic features on WAGR syndrome can be narrowed down to the region remaining intact in Patient 2. Thus, the unique genotype identified in this study suggested that haploinsufficiencies of PAX6 or PRRG4 included in this region are candidate genes for severe developmental delay and autistic features characteristic of WAGR syndrome.

PMID: 24357251 [PubMed - indexed for MEDLINE]

Sarm1, a neuronal inflammatory regulator, controls social interaction, associative memory and cognitive flexibility in mice.

November 5, 2014 - 7:08am
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Sarm1, a neuronal inflammatory regulator, controls social interaction, associative memory and cognitive flexibility in mice.

Brain Behav Immun. 2014 Mar;37:142-51

Authors: Lin CW, Hsueh YP

Abstract
Impaired neurodevelopment leads to several psychiatric disorders, including autism, schizophrenia and attention deficiency hyperactivity disorder. Our prior study showed that sterile alpha and TIR motif-containing 1 protein (Sarm1) regulates neuronal morphogenesis through at least two pathways. Sarm1 controls neuronal morphogenesis, including dendritic arborization, axonal outgrowth and establishment of neuronal polarity, through the MKK-JNK pathway. Neuronally expressed Sarm1 also regulates the expression of inflammatory cytokines in the brain, which have also been shown to impact brain development and function. Because the reduction of Sarm1 expression negatively influences neuronal development, here we investigated whether Sarm1 controls mouse behaviors. We analyzed two independent Sarm1 transgenic mouse lines using a series of behavioral assays, and found that the reduction of Sarm1 protein levels had a limited effect on locomotion and anxiety. However, Sarm1 knockdown mice exhibited impairments in cued and contextual fear conditioning as well as cognitive flexibility. Moreover, the three-chambered social test, reciprocal social interaction and social transmission of food preference further illustrated deficiencies in Sarm1 knockdown mice in social interaction. These findings suggest that Sarm1, a molecule that regulates innate immunity and neuronal morphogenesis, regulates social behaviors and cognition. We conclude that Sarm1 is involved in immune response, neural development and psychiatric disorders.

PMID: 24321214 [PubMed - indexed for MEDLINE]

Epilepsy associated with autism and attention deficit hyperactivity disorder: is there a genetic link?

November 5, 2014 - 7:08am
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Epilepsy associated with autism and attention deficit hyperactivity disorder: is there a genetic link?

Brain Dev. 2014 Mar;36(3):185-93

Authors: Lo-Castro A, Curatolo P

Abstract
Autism Spectrum Disorders (ASDs) and Attention Deficit and Hyperactivity Disorder (ADHD) are the most common comorbid conditions associated with childhood epilepsy. The co-occurrence of an epilepsy/autism phenotype or an epilepsy/ADHD phenotype has a complex and heterogeneous pathogenesis, resulting from several altered neurobiological mechanisms involved in early brain development, and influencing synaptic plasticity, neurotransmission and functional connectivity. Rare clinically relevant chromosomal aberrations, in addition to environmental factors, may confer an increased risk for ASDs/ADHD comorbid with epilepsy. The majority of the candidate genes are involved in synaptic formation/remodeling/maintenance (NRX1, CNTN4, DCLK2, CNTNAP2, TRIM32, ASTN2, CTNTN5, SYN1), neurotransmission (SYNGAP1, GABRG1, CHRNA7), or DNA methylation/chromatin remodeling (MBD5). Two genetic disorders, such as Tuberous sclerosis and Fragile X syndrome may serve as models for understanding the common pathogenic pathways leading to ASDs and ADHD comorbidities in children with epilepsy, offering the potential for new biologically focused treatment options.

PMID: 23726375 [PubMed - indexed for MEDLINE]

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