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Decoding the contribution of dopaminergic genes and pathways to autism spectrum disorder (ASD).

January 15, 2014 - 12:13pm
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Decoding the contribution of dopaminergic genes and pathways to autism spectrum disorder (ASD).

Neurochem Int. 2014 Jan 9;

Authors: Nguyen M, Roth A, Kyzar EJ, Poudel MK, Wong K, Stewart AM, Kalueff AV

Abstract
Autism spectrum disorder (ASD) is a debilitating brain illness causing social deficits, delayed development and repetitive behaviors. ASD is a heritable neurodevelopmental disorder with poorly understood and complex etiology. The central dopaminergic system is strongly implicated in ASD pathogenesis. Genes encoding various elements of this system (including dopamine receptors, the dopamine transporter or enzymes of synthesis and catabolism) have been linked to ASD. Here, we comprehensively evaluate known molecular interactors of dopaminergic genes, and identify their potential molecular partners within up/down-steam signaling pathways associated with dopamine. These in-silico analyses allowed us to construct a map of molecular pathways, regulated by dopamine and involved in ASD. Clustering these pathways reveals groups of genes associated with dopamine metabolism, encoding proteins that control dopamine neurotransmission, cytoskeletal processes, synaptic release, Ca(2+) signaling, as well as the adenosine, glutamatergic and gamma-aminobutyric systems. Overall, our analyses emphasize the important role of the dopaminergic system in ASD, and implicate several cellular signaling processes in its pathogenesis.

PMID: 24412511 [PubMed - as supplied by publisher]

DNA hypermethylation of serotonin transporter gene promoter in drug naïve patients with schizophrenia.

January 15, 2014 - 12:13pm
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DNA hypermethylation of serotonin transporter gene promoter in drug naïve patients with schizophrenia.

Schizophr Res. 2014 Jan 7;

Authors: Abdolmaleky HM, Nohesara S, Ghadirivasfi M, Lambert AW, Ahmadkhaniha H, Ozturk S, Wong CK, Shafa R, Mostafavi A, Thiagalingam S

Abstract
INTRODUCTION: Dysfunctional serotonin signaling has been linked to the pathogenesis of autism, obsessive compulsive disorder, mood disorders and schizophrenia. While the hypo-activity of serotonin signaling is involved in the pathogenesis of depression, anxiety and obsessive compulsive disorder; LSD, an agonist of serotonin type 2 receptor (5-HTR2A) induces psychosis. Therefore, anxiety and depressive disorders are treated by SSRIs which inhibit serotonin transporter (5-HTT) while psychotic disorders are controlled by drugs that block serotonin and/or dopamine receptors. Since genetic polymorphisms and epigenetic dysregulation of 5-HTT are involved in the pathogenesis of mental diseases, we analyzed DNA methylation of 5-HTT promoter in post-mortem brains and saliva samples of patients with schizophrenia (SCZ) and bipolar disorder (BD) to evaluate its potential application as a diagnostic and/or therapeutic biomarker in SCZ and BD.
METHODS: Whole genome DNA methylation profiling was performed for a total of 24 samples (including two saliva samples) using the Illumina 27K (for 12 samples) and 450K DNA methylation array platform (for another 12 samples), followed by bisulfite sequencing to identify candidate CpGs for further analysis. Quantitative methylation specific PCR (qMSP) was used to assess the degree of CpG methylation of 5-HTT promoter in 105 post-mortem brains (35 controls, 35 SCZ and 35 BD) and 100 saliva samples (30 controls, 30 SCZ, 20 BD and 20 first degree relatives of SCZ or BD). The U133 2.0 Plus Human Transcriptome array for a total of 30 post-mortem brain samples (each group 10) followed by quantitative real-time PCR was used to study 5-HTT expression in 105 post-mortem brain samples.
RESULTS: The qMSP analysis for 5-HTT promoter region showed DNA hypermethylation in post-mortem brain samples of SCZ patients (~30%), particularly in drug free patients (~60%, p=0.04). Similarly, there was a trend for DNA hypermethylation in antipsychotic free BD patients (~50%, p=0.066). qMSP analysis of DNA extracted from the saliva samples also exhibited hypermethylation of 5-HTT promoter in patients with SCZ (~30%, p=0.039), which was more significant in drug naïve SCZ patients (>50%, p=0.0025). However, the difference was not significant between the controls and unaffected first degree relatives of patients with SCZ (p=0.37) and versus patients using antipsychotic drugs (p=0.2). The whole genome transcriptome analysis of post-mortem brain samples showed reduced expression of 5-HTT in SCZ compared to the control subjects (~50%, p=0.008), confirmed by quantitative real-time PCR analysis (~40%, p=0.035) which was more significant in drug free SCZ patients (~70%, p=0.022).
CONCLUSION: A correlation between reduction in 5-HTT expression and DNA hypermethylation of the 5-HTT promoter in drug naïve SCZ patients suggests that an epigenetically defined hypo-activity of 5-HTT may be linked to SCZ pathogenesis. Furthermore, this epigenetic mark in DNA extracted from saliva can be considered as one of the key determinants in a panel of diagnostic and/or therapeutic biomarkers for SCZ.

PMID: 24411530 [PubMed - as supplied by publisher]

[Evidence for association and epistasis between the genetic markers SLC6A4 and HTR2A in autism etiology].

January 15, 2014 - 12:13pm
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[Evidence for association and epistasis between the genetic markers SLC6A4 and HTR2A in autism etiology].

Biomedica. 2012 Oct-Dec;32(4):585-601

Authors: Valencia AV, Páez AL, Sampedro ME, Ávila C, Cardona JC, Mesa C, Galvis L, Carrizosa J, Camargo M, Ruiz A, Cornejo W, Bedoya G

Abstract
INTRODUCTION: Autism spectrum disorders are severe neurodevelopmental disorders with a strong genetic component. The potential role of the serotoninergic system in the development of autistic disorder has been based on the observation of hyperserotoninemia in autistic subjects and the results of drug treatment studies. Multiple molecules involved in serotonin metabolism and neurotransmission have been studied; however, replication studies have been inconsistent. This may be partially related to the marked genetic heterogeneity of autism in different populations.
OBJECTIVES: The relationship between autism and single nucleotide polymorphisms of SLC6A4, HTR2A and ITGB3 genes was evaluated in an urban population of northwestern Colombia.
MATERIALS AND METHODS: In Antioquia, Colombia, 42 families with history of autism were screened for 10 SNPs in SLC6A4, HTR2A and ITGB3 genes and evaluated for associations with the transmission disequilibrium test. The interactions among these genes and autism was assessed with multidimensional reduction methods.
RESULTS: A significant main effect was seen among the SLC6A4 gene variants rs4583306 (OR=2.6, p=0.004) and rs2066713 (OR=2.2, p=0.03). No main effect of the ITGB3 or HTR2A variants was found, however, in the interaction effects, the SLC6A4 and HTR2A genes demonstrated significant evidence of association with autism (p<0.001).
CONCLUSION: Significant association of markers were discovered within the SLC6A4 gene and the combination of SLC6A4 and HTR2A (S-A) genes to autism. These results were consistent with previous studies conducted in other populations and provide further evidence for the implication of the serotoninergic system in the etiology of autistic disorders.

PMID: 23715234 [PubMed - indexed for MEDLINE]

Identification of single gene deletions at 15q13.3: further evidence that CHRNA7 causes the 15q13.3 microdeletion syndrome phenotype.

January 15, 2014 - 12:13pm
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Identification of single gene deletions at 15q13.3: further evidence that CHRNA7 causes the 15q13.3 microdeletion syndrome phenotype.

Clin Genet. 2013 Apr;83(4):345-51

Authors: Hoppman-Chaney N, Wain K, Seger PR, Superneau DW, Hodge JC

Abstract
The 15q13.3 microdeletion syndrome (OMIM #612001) is characterized by a wide range of phenotypic features, including intellectual disability, seizures, autism, and psychiatric conditions. This deletion is inherited in approximately 75% of cases and has been found in mildly affected and normal parents, consistent with variable expressivity and incomplete penetrance. The common deletion is approximately 2 Mb and contains several genes; however, the gene(s) responsible for the resulting clinical features have not been clearly defined. Recently, four probands were reported with small deletions including only the CHRNA7 gene. These patients showed a wide range of phenotypic features similar to those associated with the larger 15q13.3 microdeletion. To further correlate genotype and phenotype, we queried our database of >15,000 patients tested in the Mayo Clinic Cytogenetics Laboratory from 2008 to 2011 and identified 19 individuals (10 probands and 9 family members) with isolated heterozygous CHRNA7 gene deletions. All but two infants displayed multiple features consistent with 15q13.3 microdeletion syndrome. We also identified the first de novo deletion confined to CHRNA7 as well as the second known case with homozygous deletion of CHRNA7 only. These results provide further evidence implicating CHRNA7 as the gene responsible for the clinical findings associated with 15q13.3 microdeletion.

PMID: 22775350 [PubMed - indexed for MEDLINE]

Gene-environment interactions and epigenetic pathways in autism: the importance of one-carbon metabolism.

January 11, 2014 - 7:46am
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Gene-environment interactions and epigenetic pathways in autism: the importance of one-carbon metabolism.

ILAR J. 2012 Dec;53(3-4):322-40

Authors: Schaevitz LR, Berger-Sweeney JE

Abstract
Both genetic and epigenetic factors play important roles in the rate and severity of classic autism and autism spectrum disorders (ASDs). This review focuses on DNA methylation as a key epigenetic mechanism in autism. The critical role that one-carbon (C1) metabolism plays in establishing and maintaining DNA methylation patterns makes it a likely candidate pathway to regulate epigenetic processes in ASDs. This review is the first, to our knowledge, to examine how altering C1 metabolic function through genetic and environmental factors (focusing on diet) may lead to aberrant DNA methylation and increase susceptibility to ASDs. Additionally, the critical time windows for sensitivity to genetic and dietary factors both during the development of cortical networks implicated in ASDs and in regard to potential treatments are discussed. One thing is clear, if C1 metabolism plays a critical role in ASDs, it provides a potential avenue for treatment and perhaps, ultimately, prevention.

PMID: 23744970 [PubMed - indexed for MEDLINE]

New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.

January 11, 2014 - 7:46am
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New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.

PLoS One. 2013;8(5):e64685

Authors: Mejia M, Heghinian MD, Marí F, Godenschwege TA

Abstract
Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. The α7 subtype of nAChRs is involved in neurological pathologies such as Parkinson's disease, Alzheimer's disease, addiction, epilepsy and autism spectrum disorders. The Drosophila melanogaster α7 (Dα7) has the closest sequence homology to the vertebrate α7 subunit and it can form homopentameric receptors just as the vertebrate counterpart. The Dα7 subunits are essential for the function of the Giant Fiber circuit, which mediates the escape response of the fly. To further characterize the receptor function, we generated different missense mutations in the Dα7 nAChR's ligand binding domain. We characterized the effects of targeted expression of two UAS-constructs carrying a single mutation, D197A and Y195T, as well as a UAS-construct carrying a triple D77T, L117Q, I196P mutation in a Dα7 null mutant and in a wild type background. Expression of the triple mutation was able to restore the function of the circuit in Dα7 null mutants and had no disruptive effects when expressed in wild type. In contrast, both single mutations severely disrupted the synaptic transmission of Dα7-dependent but not glutamatergic or gap junction dependent synapses in wild type background, and did not or only partially rescued the synaptic defects of the null mutant. These observations are consistent with the formation of hybrid receptors, consisting of D197A or Y195T subunits and wild type Dα7 subunits, in which the binding of acetylcholine or acetylcholine-induced conformational changes of the Dα7 receptor are altered and causes inhibition of cholinergic responses. Thus targeted expression of D197A or Y195T can be used to selectively disrupt synaptic transmission of Dα7-dependent synapses in neuronal circuits. Hence, these constructs can be used as tools to study learning and memory or addiction associated behaviors by allowing the manipulation of neuronal processing in the circuits without affecting other cellular signaling.

PMID: 23737994 [PubMed - indexed for MEDLINE]

Catechol-O-methyltransferase Val158Met polymorphism and hyperactivity symptoms in Egyptian children with autism spectrum disorder.

January 11, 2014 - 7:46am
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Catechol-O-methyltransferase Val158Met polymorphism and hyperactivity symptoms in Egyptian children with autism spectrum disorder.

Res Dev Disabil. 2013 Jul;34(7):2092-7

Authors: Karam RA, Rezk NA, Abdelrahman HM, Hassan TH, Mohammad D, Hashim HM, Fattah NR

Abstract
Catechol-O-methyltransferase (COMT) plays an important role in the catabolism of brain dopamine and norepinephrine, which have been implicated in the pathogenesis of Autism spectrum disorder (ASD) as well as in other neuropsychatric disorders. We aimed to investigate the association of COMT Val158Met gene polymorphism with ASD and to examine the influence of such genotypes on hyperactivity symptoms in ASD patients. Eighty ASD patients (mean age 9 ± 1.9 years) and 100 control children (mean age 8.9 ± 1.9 years) were examined. COMT Val58Met polymorphism was genotyped using Tetra-primer ARMS-PCR method. The clinical diagnosis of ASD and ADHD were confirmed according to the DSM-IV criteria for research. We found no significant difference in genotypes or alleles' frequencies of COMT Val158Met polymorphism between ASD patients and control group. There was a significant association between COMT (Val/Val) genotype and both increasing CARS (p=0.001) and hyperactivity scores (p=0.006). Regarding Conner's Score, the DSM-IV hyperactive impulsive were significantly higher in Val/Val genotype than both Met/Val and Met/Met genotypes (p=0.03). Our data suggested an association between COMT Val58Met polymorphism and hyperactivity symptoms in Egyptian children with ASD.

PMID: 23643763 [PubMed - indexed for MEDLINE]

Autism genes keep turning up chromatin.

January 10, 2014 - 6:42am

Autism genes keep turning up chromatin.

OA Autism. 2013 Jun 19;1(2):14

Authors: Lasalle JM

Abstract
Autism-spectrum disorders (ASD) are complex genetic disorders collectively characterized by impaired social interactions and language as well as repetitive and restrictive behaviors. Of the hundreds of genes implicated in ASD, those encoding proteins acting at neuronal synapses have been most characterized by candidate gene studies. However, recent unbiased genome-wide analyses have turned up a multitude of novel candidate genes encoding nuclear factors implicated in chromatin remodeling, histone demethylation, histone variants, and the recognition of DNA methylation. Furthermore, the chromatin landscape of the human genome has been shown to influence the location of de novo mutations observed in ASD as well as the landscape of DNA methylation underlying neurodevelopmental and synaptic processes. Understanding the interactions of nuclear chromatin proteins and DNA with signal transduction pathways and environmental influences in the developing brain will be critical to understanding the relevance of these ASD candidate genes and continued uncovering of the "roots" of autism etiology.

PMID: 24404383 [PubMed - as supplied by publisher]

Sequence kernel association tests for the combined effect of rare and common variants.

January 10, 2014 - 6:42am
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Sequence kernel association tests for the combined effect of rare and common variants.

Am J Hum Genet. 2013 Jun 6;92(6):841-53

Authors: Ionita-Laza I, Lee S, Makarov V, Buxbaum JD, Lin X

Abstract
Recent developments in sequencing technologies have made it possible to uncover both rare and common genetic variants. Genome-wide association studies (GWASs) can test for the effect of common variants, whereas sequence-based association studies can evaluate the cumulative effect of both rare and common variants on disease risk. Many groupwise association tests, including burden tests and variance-component tests, have been proposed for this purpose. Although such tests do not exclude common variants from their evaluation, they focus mostly on testing the effect of rare variants by upweighting rare-variant effects and downweighting common-variant effects and can therefore lose substantial power when both rare and common genetic variants in a region influence trait susceptibility. There is increasing evidence that the allelic spectrum of risk variants at a given locus might include novel, rare, low-frequency, and common genetic variants. Here, we introduce several sequence kernel association tests to evaluate the cumulative effect of rare and common variants. The proposed tests are computationally efficient and are applicable to both binary and continuous traits. Furthermore, they can readily combine GWAS and whole-exome-sequencing data on the same individuals, when available, and are also applicable to deep-resequencing data of GWAS loci. We evaluate these tests on data simulated under comprehensive scenarios and show that compared with the most commonly used tests, including the burden and variance-component tests, they can achieve substantial increases in power. We next show applications to sequencing studies for Crohn disease and autism spectrum disorders. The proposed tests have been incorporated into the software package SKAT.

PMID: 23684009 [PubMed - indexed for MEDLINE]

[Brain development before onset of the first psychotic episode and during outcome of schizophrenia].

January 9, 2014 - 3:19pm
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[Brain development before onset of the first psychotic episode and during outcome of schizophrenia].

Fortschr Neurol Psychiatr. 2013 May;81(5):260-4

Authors: Falkai P, Reich-Erkelenz D, Malchow B, Schmitt A, Majtenyi K

Abstract
A circumscribed association between copy number variations and the diagnosis of schizophrenia or autism but not bipolar disorder supports the notion of schizophrenia and autism principally representing a disturbed brain development. Data of multiply affected families show certain brain structural (e. g. hippocampal) changes to also be present in their first-grade relatives without leading to psychopathological abnormalities. It thus can be concluded that there exist regional fronto-temporal changes in schizophrenia due to genetically early determined primary vulnerability. The transition of this vulnerability into a prodrome to the point of the fully developed disease is triggered by relevant environmental factors. Hippocampal brain structural changes do not base on neuronal loss, for which reason the underlying mechanism might be a reduction of neuropil and thus a disturbance of synaptic processes or even regenerative mechanisms. Thus, disturbed regenerative mechanisms might be linked to the course of schizophrenic psychosis: the more pronounced the negative symptoms, the more evident the impaired synaptic or neuronal plasticity. Based on initial data we speculate the disturbed synaptic/plastic processes to result from an impaired epigenetic regulation. This could explain how relevant environmental factors (pregnancy and birth complications, early childhood abuse or cannabis abuse) via risk genes might lead to a destabilized neuronal network which in the end could trigger schizophrenia symptoms on the behavioral level.

PMID: 23695790 [PubMed - indexed for MEDLINE]

Increased genome instability in human DNA segments with self-chains: homology-induced structural variations via replicative mechanisms.

January 8, 2014 - 6:14am
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Increased genome instability in human DNA segments with self-chains: homology-induced structural variations via replicative mechanisms.

Hum Mol Genet. 2013 Jul 1;22(13):2642-51

Authors: Zhou W, Zhang F, Chen X, Shen Y, Lupski JR, Jin L

Abstract
Environmental factors including ionizing radiation and chemical agents have been known to be able to induce DNA rearrangements and cause genomic structural variations (SVs); however, the roles of intrinsic characteristics of the human genome, such as regional genome architecture, in SV formation and the potential mechanisms underlying genomic instability remain to be further elucidated. Recently, locus-specific observations showed that 'self-chain' (SC), a group of short low-copy repeats (LCRs) in the human genome, can induce autism-associated SV mutations of the MECP2 and NRXN1 genes. In this study, we conducted a genome-wide analysis to investigate SCs and their potential roles in genomic SV formation. Utilizing a vast amount of human SV data, we observed a significant biased distribution of human germline SV breakpoints to SC regions. Notably, the breakpoint distribution pattern is different between SV types across deletion, duplication, inversion and insertion. Our observations were coincident with a mechanism of SC-induced DNA replicative errors, whereas SC may sporadically be used as substrates of nonallelic homologous recombination (NAHR). This contention was further supported by our consistent findings in somatic SV mutations of cancer genomes, suggesting a general mechanism of SC-induced genome instability in human germ and somatic cells.

PMID: 23474816 [PubMed - indexed for MEDLINE]

A de novo convergence of autism genetics and molecular neuroscience.

January 7, 2014 - 6:00am

A de novo convergence of autism genetics and molecular neuroscience.

Trends Neurosci. 2013 Dec 30;

Authors: Krumm N, O'Roak BJ, Shendure J, Eichler EE

Abstract
Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental disorders with large genetic components, but identification of pathogenic genes has proceeded slowly because hundreds of loci are involved. New exome sequencing technology has identified novel rare variants and has found that sporadic cases of ASD/ID are enriched for disruptive de novo mutations. Targeted large-scale resequencing studies have confirmed the significance of specific loci, including chromodomain helicase DNA binding protein 8 (CHD8), sodium channel, voltage-gated, type II, alpha subunit (SCN2A), dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), and catenin (cadherin-associated protein), beta 1, 88kDa (CTNNB1, beta-catenin). We review recent studies and suggest that they have led to a convergence on three functional pathways: (i) chromatin remodeling; (ii) wnt signaling during development; and (iii) synaptic function. These pathways and genes significantly expand the neurobiological targets for study, and suggest a path for future genetic and functional studies.

PMID: 24387789 [PubMed - as supplied by publisher]

Heterozygous FA2H mutations in autism spectrum disorders.

January 7, 2014 - 6:00am
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Heterozygous FA2H mutations in autism spectrum disorders.

BMC Med Genet. 2013;14:124

Authors: Scheid I, Maruani A, Huguet G, Leblond CS, Nygren G, Anckarsäter H, Beggiato A, Rastam M, Amsellem F, Gillberg IC, Elmaleh M, Leboyer M, Gillberg C, Betancur C, Coleman M, Hama H, Cook EH, Bourgeron T, Delorme R

Abstract
BACKGROUND: Widespread abnormalities in white matter development are frequently reported in cases of autism spectrum disorders (ASD) and could be involved in the disconnectivity suggested in these disorders. Homozygous mutations in the gene coding for fatty-acid 2-hydroxylase (FA2H), an enzyme involved in myelin synthesis, are associated with complex leukodystrophies, but little is known about the functional impact of heterozygous FA2H mutations. We hypothesized that rare deleterious heterozygous mutations of FA2H might constitute risk factors for ASD.
METHODS: We searched deleterious mutations affecting FA2H, by genotyping 1256 independent patients with ASD genotyped using Genome Wide SNP arrays, and also by sequencing in independent set of 186 subjects with ASD and 353 controls. We then explored the impact of the identified mutations by measuring FA2H enzymatic activity and expression, in transfected COS7 cells.
RESULTS: One heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. Also, two rare non-synonymous mutations (R113W and R113Q) were reported. Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells.
CONCLUSIONS: While our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.

PMID: 24299421 [PubMed - indexed for MEDLINE]

Random or Stochastic Monoallelic Expressed Genes Are Enriched for Neurodevelopmental Disorder Candidate Genes.

January 5, 2014 - 11:35am
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Random or Stochastic Monoallelic Expressed Genes Are Enriched for Neurodevelopmental Disorder Candidate Genes.

PLoS One. 2013;8(12):e85093

Authors: Jeffries AR, Collier DA, Vassos E, Curran S, Ogilvie CM, Price J

Abstract
Random or stochastic monoallelic expressed genes (StMA genes) represent a unique form of monoallelic expression where allelic choice is made at random early in development. The consequential clonal diversity provides opportunity for functional heterozygosity in tissues such as the brain, and can impact on both development and disease. We investigate the relationship of StMA expressed genes previously identified in clonal neural stem cells with the neurodevelopmental disorders autism and schizophrenia. We found that StMA genes show an overrepresentation of schizophrenia risk candidates identified by genome wide association studies from the genetic association database. Similar suggestive enrichment was also found for genes from the NHGRI genome-wide association study catalog and a psychiatric genetics consortium schizophrenia dataset although these latter more robust gene lists did not achieve statistical significance. We also examined multiple sources of copy number variation (CNV) datasets from autism and schizophrenia cohorts. After taking into account total gene numbers and CNV size, both autism and schizophrenia associated CNVs appeared to show an enrichment of StMA genes relative to the control CNV datasets. Since the StMA genes were originally identified in neural stem cells, bias due to the neural transcriptome is possible. To address this, we randomly sampled neural stem cell expressed genes and repeated the tests. After a significant number of iterations, neural stem cell expressed genes did not show an overrepresentation in autism or schizophrenia CNV datasets. Therefore, irrespective of the neural derived transcriptome, StMA genes originally identified in neural stem cells show an overrepresentation in CNVs associated with autism and schizophrenia. If this association is functional, then the regulation (or dysregulation) of this form of allelic expression status within tissues such as the brain may be a contributory risk factor for neurodevelopmental disorders and may also influence disease discordance sometimes observed in monozygotic twins.

PMID: 24386451 [PubMed - as supplied by publisher]

Epigenetic factors and autism spectrum disorders.

January 5, 2014 - 11:35am
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Epigenetic factors and autism spectrum disorders.

Neuromolecular Med. 2013 Jun;15(2):339-50

Authors: Flashner BM, Russo ME, Boileau JE, Leong DW, Gallicano GI

Abstract
Autism is a complex neurodevelopmental disorder that has significant phenotypic overlap with several diseases, many of which fall within the broader category of autism spectrum disorders (ASDs). The etiology of the disorder is unclear and seems to involve a complex interplay of polygenic as well as environmental factors. We discuss evidence that suggests that epigenetic dysregulation is highly implicated as a contributing cause of ASDs and autism. Specifically, we examine neurodevelopmental disorders that share significant phenotypic overlap with ASDs and feature the dysregulation of epigenetically modified genes including UBE3A, GABA receptor genes, and RELN. We then look at the dysregulated expression of implicated epigenetic modifiers, namely MeCP2, that yield complex and varied downstream pleiotropic effects. Finally, we examine epigenetically mediated parent-of-origin effects through which paternal gene expression dominates that of maternal contributing to contrasting phenotypes implicated in ASDs. Such preliminary evidence suggests that elucidating the complex role of epigenetic regulations involved in ASDs could prove vital in furthering our understanding of the complex etiology of autism and ASDs.

PMID: 23468062 [PubMed - indexed for MEDLINE]

Exploring the multifactorial nature of autism through computational systems biology: calcium and the Rho GTPase RAC1 under the spotlight.

January 5, 2014 - 11:35am
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Exploring the multifactorial nature of autism through computational systems biology: calcium and the Rho GTPase RAC1 under the spotlight.

Neuromolecular Med. 2013 Jun;15(2):364-83

Authors: Zeidán-Chuliá F, Rybarczyk-Filho JL, Salmina AB, de Oliveira BH, Noda M, Moreira JC

Abstract
Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication accompanied with repetitive behavioral patterns and unusual stereotyped interests. Autism is considered a highly heterogeneous disorder with diverse putative causes and associated factors giving rise to variable ranges of symptomatology. Incidence seems to be increasing with time, while the underlying pathophysiological mechanisms remain virtually uncharacterized (or unknown). By systematic review of the literature and a systems biology approach, our aims were to examine the multifactorial nature of autism with its broad range of severity, to ascertain the predominant biological processes, cellular components, and molecular functions integral to the disorder, and finally, to elucidate the most central contributions (genetic and/or environmental) in silico. With this goal, we developed an integrative network model for gene-environment interactions (GENVI model) where calcium (Ca(2+)) was shown to be its most relevant node. Moreover, considering the present data from our systems biology approach together with the results from the differential gene expression analysis of cerebellar samples from autistic patients, we believe that RAC1, in particular, and the RHO family of GTPases, in general, could play a critical role in the neuropathological events associated with autism.

PMID: 23456597 [PubMed - indexed for MEDLINE]

Paroxysmal periodic dystonic postures in an infant with 18q23 deletion syndrome.

January 5, 2014 - 11:35am
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Paroxysmal periodic dystonic postures in an infant with 18q23 deletion syndrome.

Neuropediatrics. 2013 Jun;44(3):163-6

Authors: Ishikawa N, Kobayashi Y, Fujii Y, Kobayashi M

Abstract
The 18q23 deletion syndrome is characterized by diverse neurological and psychiatric features, including developmental delays, epilepsy, and autism. We report on a female infant with an 18q23 deletion who displayed atypical periodic dystonic postures. Video-electroencephalography recordings were used to evaluate the involuntary nonepileptic movements in the infant. Although nonepileptic involuntary movements have been rarely reported in adult patients, there are no reports of paroxysmal periodic dystonia in infants with 18q23 deletion. This study suggests that clustered periodic dystonia should be clinically recognized as a phenotypic feature in some patients with 18q23 deletion syndrome.

PMID: 23117893 [PubMed - indexed for MEDLINE]

Familial KANK1 deletion that does not follow expected imprinting pattern.

January 3, 2014 - 7:55am
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Familial KANK1 deletion that does not follow expected imprinting pattern.

Eur J Med Genet. 2013 May;56(5):256-9

Authors: Vanzo RJ, Martin MM, Sdano MR, South ST

Abstract
Deletion of the KANK1 gene (also called ANKRD15), located at chromosome position 9p24.3, has been associated with neurodevelopmental disease including congenital cerebral palsy, hypotonia, quadriplegia, and intellectual disability in a four-generation family. The inheritance pattern in this family was suggested to be maternal imprinting, as all affected individuals inherited the deletion from their fathers and monoallelic protein expression was observed. We present a family in which the proband's phenotype, including autism spectrum disorder, motor delay, and intellectual disability, is consistent with this previous report of KANK1 deletions. However, a paternally inherited deletion in the proband's unaffected sibling did not support maternal imprinting. This family raises consideration of further complexity of the KANK1 locus, including variable expressivity, incomplete penetrance, and the additive effects of additional genomic variants or the potential benign nature of inherited copy number variations (CNVs). However, when considered with the previous publication, our case also suggests that KANK1 may be subject to random monoallelic expression as a possible mode of inheritance. It is also important to consider that KANK1 has two alternately spliced transcripts, A and B. These have differential tissue expression and thus potentially differential clinical significance. Based upon cases in the literature, the present case, and information in the Database of Genomic Variants, it is possible that only aberrations of variant A contribute to neurodevelopmental disease. The familial deletion in this present case does not support maternal imprinting as an inheritance pattern. We suggest that other inheritance patterns and caveats should be considered when evaluating KANK1 deletions, which may become increasingly recognized through whole genome microarray testing, whole genome sequencing, and whole exome sequencing techniques.

PMID: 23454270 [PubMed - indexed for MEDLINE]

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