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Fragile X syndrome due to a missense mutation.

June 13, 2015 - 7:13am
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Fragile X syndrome due to a missense mutation.

Eur J Hum Genet. 2014 Oct;22(10):1185-9

Authors: Myrick LK, Nakamoto-Kinoshita M, Lindor NM, Kirmani S, Cheng X, Warren ST

Abstract
Fragile X syndrome is a common inherited form of intellectual disability and autism spectrum disorder. Most patients exhibit a massive CGG-repeat expansion mutation in the FMR1 gene that silences the locus. In over two decades since the discovery of FMR1, only a single missense mutation (p.(Ile304Asn)) has been reported as causing fragile X syndrome. Here we describe a 16-year-old male presenting with fragile X syndrome but without the repeat expansion mutation. Rather, we find a missense mutation, c.797G>A, that replaces glycine 266 with glutamic acid (p.(Gly266Glu)). The Gly266Glu FMR protein abolished many functional properties of the protein. This patient highlights the diagnostic utility of FMR1 sequencing.

PMID: 24448548 [PubMed - indexed for MEDLINE]

Human Chromosome Y and Haplogroups; introducing YDHS Database.

June 11, 2015 - 6:16am

Human Chromosome Y and Haplogroups; introducing YDHS Database.

Clin Transl Med. 2015 Dec;4(1):60

Authors: Tiirikka T, Moilanen JS

Abstract
BACKGROUND: As the high throughput sequencing efforts generate more biological information, scientists from different disciplines are interpreting the polymorphisms that make us unique. In addition, there is an increasing trend in general public to research their own genealogy, find distant relatives and to know more about their biological background. Commercial vendors are providing analyses of mitochondrial and Y-chromosomal markers for such purposes. Clearly, an easy-to-use free interface to the existing data on the identified variants would be in the interest of general public and professionals less familiar with the field. Here we introduce a novel metadatabase YDHS that aims to provide such an interface for Y-chromosomal DNA (Y-DNA) haplogroups and sequence variants.
METHODS: The database uses ISOGG Y-DNA tree as the source of mutations and haplogroups and by using genomic positions of the mutations the database links them to genes and other biological entities. YDHS contains analysis tools for deeper Y-SNP analysis.
RESULTS: YDHS addresses the shortage of Y-DNA related databases. We have tested our database using a set of different cases from literature ranging from infertility to autism. The database is at http://www.semanticgen.net/ydhs CONCLUSIONS: Y-chromosomal DNA (Y-DNA) haplogroups and sequence variants have not been in the scientific limelight, excluding certain specialized fields like forensics, mainly because there is not much freely available information or it is scattered in different sources. However, as we have demonstrated Y-SNPs do play a role in various cases on the haplogroup level and it is possible to create a free Y-DNA dedicated bioinformatics resource.

PMID: 26061870 [PubMed - as supplied by publisher]

Investigation of Gene Regulatory Networks Associated with Autism Spectrum Disorder Based on MiRNA Expression in China.

June 11, 2015 - 6:16am

Investigation of Gene Regulatory Networks Associated with Autism Spectrum Disorder Based on MiRNA Expression in China.

PLoS One. 2015;10(6):e0129052

Authors: Huang F, Long Z, Chen Z, Li J, Hu Z, Qiu R, Zhuang W, Tang B, Xia K, Jiang H

Abstract
Autism spectrum disorder (ASD) comprise a group of neurodevelopmental disorders characterized by deficits in social and communication capacities and repetitive behaviors. Increasing neuroscientific evidence indicates that the neuropathology of ASD is widespread and involves epigenetic regulation in the brain. Differentially expressed miRNAs in the peripheral blood from autism patients were identified by high-throughput miRNA microarray analyses. Five of these miRNAs were confirmed through quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. A search for candidate target genes of the five confirmed miRNAs was performed through a Kyoto encyclopedia of genes and genomes (KEGG) biological pathways and Gene Ontology enrichment analysis of gene function to identify gene regulatory networks. To the best of our knowledge, this study provides the first global miRNA expression profile of ASD in China. The differentially expressed miR-34b may potentially explain the higher percentage of male ASD patients, and the aberrantly expressed miR-103a-3p may contribute to the abnormal ubiquitin-mediated proteolysis observed in ASD.

PMID: 26061495 [PubMed - as supplied by publisher]

DPP6 gene disruption in a family with Gilles de la Tourette syndrome.

June 11, 2015 - 6:16am
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DPP6 gene disruption in a family with Gilles de la Tourette syndrome.

Neurogenetics. 2014 Oct;15(4):237-42

Authors: Prontera P, Napolioni V, Ottaviani V, Rogaia D, Fusco C, Augello B, Serino D, Parisi V, Bernardini L, Merla G, Cavanna AE, Donti E

Abstract
Gilles de la Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor and vocal tics, frequently associated with psychiatric co-morbidities. Despite the significant level of heritability, the genetic architecture of TS still remains elusive. Herein, we investigated an Italian family where an 8-year-old boy, his father, and paternal uncle have a diagnosis of TS. Array-CGH and high resolution SNP-array analyses revealed a heterozygous microdeletion of ∼135 kb at the 7q36.2 locus in the proband and his father. Fluorescent in situ hybridization and quantitative PCR (qPCR) analyses confirmed the presence of the alteration also in the paternal uncle. The deletion selectively involves the first exon of the DPP6 gene, leading to a down-regulation of its expression, as demonstrated by the reduced messenger RNA (mRNA) levels assessed by RT-qPCR. The DPP6 gene encodes for a type II membrane glycoprotein expressed predominantly in the central nervous system. To date, a de novo DPP6 exonic duplication, of uncertain significance, was reported in one patient with TS. Moreover, the DPP6 gene has been implicated in the pathogenesis of autism spectrum disorder (ASD) and, notably, in haloperidol-induced dyskinesia. This first familial case provides evidence for association between DPP6 haploinsufficiency and TS, further suggesting a plausible molecular link between TS and ASD, and might shed some light on the efficacy and tolerability profiles of antidopaminergic agents used for tic management, thus prompting further studies on a larger cohort of patients.

PMID: 25129042 [PubMed - indexed for MEDLINE]

Fetal DNA methylation of autism spectrum disorders candidate genes: association with spontaneous preterm birth.

June 10, 2015 - 10:42am
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Fetal DNA methylation of autism spectrum disorders candidate genes: association with spontaneous preterm birth.

Am J Obstet Gynecol. 2015 Apr;212(4):533.e1-9

Authors: Behnia F, Parets SE, Kechichian T, Yin H, Dutta EH, Saade GR, Smith AK, Menon R

Abstract
OBJECTIVE: Autism spectrum disorder (ASD) is associated with preterm birth (PTB), although the reason underlying this relationship is still unclear. Our objective was to examine DNA methylation patterns of 4 ASD candidate genes in human fetal membranes from spontaneous PTB and uncomplicated term birth.
STUDY DESIGN: A literature search for genes that have been implicated in ASD yielded 14 candidate genes (OXTR, SHANK3, BCL2, RORA, EN2, RELN, MECP2, AUTS2, NLGN3, NRXN1, SLC6A4, UBE3A, GABA, AFF2) that were epigenetically modified in relation to ASD. DNA methylation in fetal leukocyte DNA in 4 of these genes (OXTR, SHANK3, BCL2, and RORA) was associated with PTB in a previous study. This study evaluated DNA methylation, transcription (reverse transcription polymerase chain reaction), and translation patterns (immunostaining and Western blot) in fetal membrane from term labor (n = 14), term not in labor (TNIL; n = 29), and spontaneous preterm birth (PTB; n = 27). Statistical analysis was performed with analysis of variance; a probability value of < .05 was significant.
RESULTS: Higher methylation of the OXTR promoter was seen in fetal membranes from PTB, compared with term labor or TNIL. No other gene showed any methylation differences among groups. Expression of OXTR was not different among groups, but the 70 kDa OXTR protein was seen only in PTB, and immunostaining was more intense in PTB amniocytes than term labor or TNIL.
CONCLUSION: Among the 4 genes that were studied, fetal membranes from PTB demonstrate differences in OXTR methylation and regulation and expression, which suggest that epigenetic alteration of this gene in fetal membrane may likely be indicating an in utero programing of this gene and serve as a surrogate in a subset of PTB. The usefulness of OXTR hypermethylation as a surrogate for a link to ASD should be further evaluated in longitudinal and in vitro studies.

PMID: 25687563 [PubMed - indexed for MEDLINE]

Consensus Genotyper for Exome Sequencing (CGES): improving the quality of exome variant genotypes.

June 10, 2015 - 7:21am
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Consensus Genotyper for Exome Sequencing (CGES): improving the quality of exome variant genotypes.

Bioinformatics. 2015 Jan 15;31(2):187-93

Authors: Trubetskoy V, Rodriguez A, Dave U, Campbell N, Crawford EL, Cook EH, Sutcliffe JS, Foster I, Madduri R, Cox NJ, Davis LK

Abstract
MOTIVATION: The development of cost-effective next-generation sequencing methods has spurred the development of high-throughput bioinformatics tools for detection of sequence variation. With many disparate variant-calling algorithms available, investigators must ask, 'Which method is best for my data?' Machine learning research has shown that so-called ensemble methods that combine the output of multiple models can dramatically improve classifier performance. Here we describe a novel variant-calling approach based on an ensemble of variant-calling algorithms, which we term the Consensus Genotyper for Exome Sequencing (CGES). CGES uses a two-stage voting scheme among four algorithm implementations. While our ensemble method can accept variants generated by any variant-calling algorithm, we used GATK2.8, SAMtools, FreeBayes and Atlas-SNP2 in building CGES because of their performance, widespread adoption and diverse but complementary algorithms.
RESULTS: We apply CGES to 132 samples sequenced at the Hudson Alpha Institute for Biotechnology (HAIB, Huntsville, AL) using the Nimblegen Exome Capture and Illumina sequencing technology. Our sample set consisted of 40 complete trios, two families of four, one parent-child duo and two unrelated individuals. CGES yielded the fewest total variant calls (N(CGES) = 139° 897), the highest Ts/Tv ratio (3.02), the lowest Mendelian error rate across all genotypes (0.028%), the highest rediscovery rate from the Exome Variant Server (EVS; 89.3%) and 1000 Genomes (1KG; 84.1%) and the highest positive predictive value (PPV; 96.1%) for a random sample of previously validated de novo variants. We describe these and other quality control (QC) metrics from consensus data and explain how the CGES pipeline can be used to generate call sets of varying quality stringency, including consensus calls present across all four algorithms, calls that are consistent across any three out of four algorithms, calls that are consistent across any two out of four algorithms or a more liberal set of all calls made by any algorithm.
AVAILABILITY AND IMPLEMENTATION: To enable accessible, efficient and reproducible analysis, we implement CGES both as a stand-alone command line tool available for download in GitHub and as a set of Galaxy tools and workflows configured to execute on parallel computers.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 25270638 [PubMed - indexed for MEDLINE]

The landscape of copy number variations in Finnish families with autism spectrum disorders.

June 9, 2015 - 8:47am

The landscape of copy number variations in Finnish families with autism spectrum disorders.

Autism Res. 2015 Jun 6;

Authors: Kanduri C, Kantojärvi K, Salo PM, Vanhala R, Buck G, Blancher C, Lähdesmäki H, Järvelä I

Abstract
Rare de novo and inherited copy number variations (CNVs) have been implicated in autism spectrum disorder (ASD) risk. However, the genetic underpinnings of ASD remain unknown in more than 80% of cases. Therefore, identification of novel candidate genes and corroboration of known candidate genes may broaden the horizons of determining genetic risk alleles, and subsequent development of diagnostic testing. Here, using genotyping arrays, we characterized the genetic architecture of rare CNVs (<1% frequency) in a Finnish case-control dataset. Unsurprisingly, ASD cases harbored a significant excess of rare, large (>1 Mb) CNVs and rare, exonic CNVs. The exonic rare de novo CNV rate (∼22.5%) seemed higher compared to previous reports. We identified several CNVs in well-known ASD regions including GSTM1-5, DISC1, FHIT, RBFOX1, CHRNA7, 15q11.2, 15q13.2-q13.3, 17q12, and 22q11.21. Additionally, several novel candidate genes (BDKRB1, BDKRB2, AP2M1, SPTA1, PTH1R, CYP2E1, PLCD3, F2RL1, UQCRC2, LILRB3, RPS9, and COL11A2) were identified through gene prioritization. The majority of these genes belong to neuroactive ligand-receptor interaction pathways, and calcium signaling pathways, thus suggesting that a subset of these novel candidate genes may contribute to ASD risk. Furthermore, several metabolic pathways like caffeine metabolism, drug metabolism, retinol metabolism, and calcium-signaling pathway were found to be affected by the rare exonic ASD CNVs. Additionally, biological processes such as bradykinin receptor activity, endoderm formation and development, and oxidoreductase activity were enriched among the rare exonic ASD CNVs. Overall, our findings may add data about new genes and pathways that contribute to the genetic architecture of ASD. Autism Res 2015. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 26052927 [PubMed - as supplied by publisher]

Underlying Factors Behind the Low Prevalence of Autism Spectrum Disorders in Oman: Sociocultural perspective.

June 9, 2015 - 8:47am

Underlying Factors Behind the Low Prevalence of Autism Spectrum Disorders in Oman: Sociocultural perspective.

Sultan Qaboos Univ Med J. 2015 May;15(2):e213-7

Authors: Ouhtit A, Al-Farsi Y, Al-Sharbati M, Waly M, Gupta I, Al-Farsi O, Al-Khaduri M, Al-Shafaee M, Al-Adawi S

Abstract
Epidemiological surveys from various countries indicate an increased prevalence of autism spectrum disorders (ASD), leading researchers to debate whether there are now 'more affected' or 'more detected'. The epidemiology of ASD in developing countries, such as Oman, has generally indicated a lower prevalence compared to developed countries in the West. In Oman, the prevalence is low; however, this article highlights some of the factors that could contribute to the appearance of a low ASD rate: cross-cultural variations in the presentation of distress; a lack of reliable biological markers for diagnosing ASD, and a lack of health services for children with ASD, thus limiting the number of participants in epidemiological surveys. While the defining features of ASD have yet to be established, pilot studies in Oman indicate a substantial number of children with these disorders. Therefore, it is important that these discrepancies be addressed and the need for appropriate services for this patient population in Oman be highlighted.

PMID: 26052454 [PubMed]

Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism.

June 9, 2015 - 8:47am

Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism.

Mol Autism. 2015;6:33

Authors: Mottron L, Duret P, Mueller S, Moore RD, Forgeot d'Arc B, Jacquemont S, Xiong L

Abstract
Several observations support the hypothesis that differences in synaptic and regional cerebral plasticity between the sexes account for the high ratio of males to females in autism. First, males are more susceptible than females to perturbations in genes involved in synaptic plasticity. Second, sex-related differences in non-autistic brain structure and function are observed in highly variable regions, namely, the heteromodal associative cortices, and overlap with structural particularities and enhanced activity of perceptual associative regions in autistic individuals. Finally, functional cortical reallocations following brain lesions in non-autistic adults (for example, traumatic brain injury, multiple sclerosis) are sex-dependent. Interactions between genetic sex and hormones may therefore result in higher synaptic and consecutively regional plasticity in perceptual brain areas in males than in females. The onset of autism may largely involve mutations altering synaptic plasticity that create a plastic reaction affecting the most variable and sexually dimorphic brain regions. The sex ratio bias in autism may arise because males have a lower threshold than females for the development of this plastic reaction following a genetic or environmental event.

PMID: 26052415 [PubMed]

Association of NCAM1 polymorphisms with autism and parental age at conception in a Chinese Han population.

June 9, 2015 - 8:47am
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Association of NCAM1 polymorphisms with autism and parental age at conception in a Chinese Han population.

Genet Test Mol Biomarkers. 2014 Oct;18(10):690-4

Authors: Zhang J, Wang A, Li Y, Lu X, Wang F, Fang F

Abstract
AIMS: The neural cell adhesion molecule (NCAM) has been reported to be involved in the development of the central nervous system and its mRNA level might decrease in the serum of autistic patients. However, there was no evidence of the association of the NCAM1 gene polymorphisms with autism. In the present study, we enrolled 237 children with autism and 451 healthy control subjects. Then, we used the direct DNA sequencing for genotyping five tag single-nucleotide polymorphisms (SNPs) in the NCAM1 gene.
RESULTS: By using case-control association analyses, we found that three SNPs at the NCAM1 gene were associated with autism (rs 4937786, p=0.015; rs 12418058, p=0.0076; rs 1436109, p=0.0023). Two of them remained significant after the Bonferroni multiple testing correction (rs 12418058, P(corrected) =0.038; rs 1436109, P(corrected) =0.012). Moreover, two of the SNPs were associated with the parental age at conception in autism (rs 12418058, p=0.037; rs 1436109, p=0.01).
CONCLUSION: These results showed that NCAM1 might play an important role in the pathogenesis of autism.

PMID: 25137309 [PubMed - indexed for MEDLINE]

The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders.

June 8, 2015 - 7:35am

The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders.

Neuron. 2015 Jun 3;86(5):1119-1130

Authors: Braat S, Kooy RF

Abstract
Intellectual disability, autism spectrum disorder, and epilepsy are prime examples of neurodevelopmental disorders that collectively affect a significant percentage of the world population. Recent technological breakthroughs allowed the elucidation of the genetic causes of many of these disorders. As neurodevelopmental disorders are genetically heterogeneous, the development of rational therapy is extremely challenging. Fortunately, many causative genes are interconnected and cluster in specific cellular pathways. Targeting a common node in such a network would allow us to interfere with a series of related neurodevelopmental disorders at once. Here, we argue that the GABAergic system is disturbed in many neurodevelopmental disorders, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and is a key candidate target for therapeutic intervention. Many drugs that modulate the GABAergic system have already been tested in animal models with encouraging outcomes and are readily available for clinical trials.

PMID: 26050032 [PubMed - as supplied by publisher]

Recessive DEAF1 mutation associates with autism, intellectual disability, basal ganglia dysfunction and epilepsy.

June 7, 2015 - 6:14am

Recessive DEAF1 mutation associates with autism, intellectual disability, basal ganglia dysfunction and epilepsy.

J Med Genet. 2015 Jun 5;

Authors: Rajab A, Schuelke M, Gill E, Zwirner A, Seifert F, Morales Gonzalez S, Knierim E

Abstract
BACKGROUND: Various genetic defects cause autism associated with intellectual disability and epilepsy. Here, we set out to identify the genetic defect in a consanguineous Omani family with three affected children in whom mutations in known candidate genes had been excluded beforehand.
METHODS: For mutation screening, we combined autozygosity mapping and whole exome sequencing. Segregation of potential disease variants with the phenotype was verified by Sanger sequencing. A splice-site mutation was confirmed and quantified by qPCR.
RESULTS: We found an autosomal recessive splice acceptor mutation in DEAF1 (c.997+4A>C, p.G292Pfs*) in all affected individuals, which led to exon skipping, and reduced the normal full-length mRNA copy number in the patients to 5% of the wild-type level. Besides intellectual disability and autism, two of three affected siblings suffered from severe epilepsy. All patients exhibited dyskinesia of the limbs coinciding with symmetric T2 hyperintensities of the basal ganglia on cranial MRI.
CONCLUSIONS: A recent report has shown dominant DEAF1 mutations to occur de novo in patients with intellectual disability. Here, we demonstrate that a DEAF1-associated disorder can also be inherited as an autosomal recessive trait with heterozygous individuals being entirely healthy. Our findings expand the clinical and genetic spectrum of DEAF1 mutations to comprise epilepsy and extrapyramidal symptoms.

PMID: 26048982 [PubMed - as supplied by publisher]

Using Gene Ontology to describe the role of the neurexin-neuroligin-SHANK complex in human, mouse and rat and its relevance to autism.

June 7, 2015 - 6:14am

Using Gene Ontology to describe the role of the neurexin-neuroligin-SHANK complex in human, mouse and rat and its relevance to autism.

BMC Bioinformatics. 2015;16(1):186

Authors: Patel S, Roncaglia P, Lovering RC

Abstract
BACKGROUND: People with an autistic spectrum disorder (ASD) display a variety of characteristic behavioral traits, including impaired social interaction, communication difficulties and repetitive behavior. This complex neurodevelopment disorder is known to be associated with a combination of genetic and environmental factors. Neurexins and neuroligins play a key role in synaptogenesis and neurexin-neuroligin adhesion is one of several processes that have been implicated in autism spectrum disorders.
RESULTS: In this report we describe the manual annotation of a selection of gene products known to be associated with autism and/or the neurexin-neuroligin-SHANK complex and demonstrate how a focused annotation approach leads to the creation of more descriptive Gene Ontology (GO) terms, as well as an increase in both the number of gene product annotations and their granularity, thus improving the data available in the GO database.
CONCLUSIONS: The manual annotations we describe will impact on the functional analysis of a variety of future autism-relevant datasets. Comprehensive gene annotation is an essential aspect of genomic and proteomic studies, as the quality of gene annotations incorporated into statistical analysis tools affects the effective interpretation of data obtained through genome wide association studies, next generation sequencing, proteomic and transcriptomic datasets.

PMID: 26047810 [PubMed - as supplied by publisher]

Sleep in Autism Spectrum Disorders.

June 6, 2015 - 7:23am
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Sleep in Autism Spectrum Disorders.

Curr Sleep Med Rep. 2015 Jun;1(2):131-140

Authors: Veatch OJ, Maxwell-Horn AC, Malow BA

Abstract
Autism spectrum disorders (ASD) are common neurodevelopmental conditions, affecting 1 in 68 children. Sleep disturbance, particularly insomnia, is very common in children diagnosed with ASD, with evidence supporting overlapping neurobiological and genetic underpinnings. Disturbed sleep exacerbates core and related ASD symptoms and has a substantial negative impact on the entire family. Treatment of sleep disturbance holds promise for ameliorating many of the challenging behavioral symptoms that children with ASD and their families face. Behavioral and pharmacological studies indicate promising approaches to treating sleep disturbances in this population. Awareness of treatment options is particularly important as parents and clinicians may believe that sleep disturbance is part of autism and refractory to therapy. In addition, autism symptoms refractory to treatment with conventional psychiatric medications may improve when sleep is addressed. Additional evidence-based studies are needed, including those that address the underlying biology of this condition.

PMID: 26046012 [PubMed - as supplied by publisher]

Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID.

June 6, 2015 - 7:23am
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Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID.

Mol Autism. 2015;6:23

Authors: Cochoy DM, Kolevzon A, Kajiwara Y, Schoen M, Pascual-Lucas M, Lurie S, Buxbaum JD, Boeckers TM, Schmeisser MJ

Abstract
BACKGROUND: SHANK proteins are crucial for the formation and plasticity of excitatory synapses. Although mutations in all three SHANK genes are associated with autism spectrum disorder (ASD), SHANK3 appears to be the major ASD gene with a prevalence of approximately 0.5% for SHANK3 mutations in ASD, with higher rates in individuals with ASD and intellectual disability (ID). Interestingly, the most relevant mutations are typically de novo and often are frameshift or nonsense mutations resulting in a premature stop and a truncation of SHANK3 protein.
METHODS: We analyzed three different SHANK3 stop mutations that we identified in individuals with ASD and/or ID, one novel (c.5008A > T) and two that we recently described (c.1527G > A, c.2497delG). The mutations were inserted into the human SHANK3a sequence and analyzed for effects on subcellular localization and neuronal morphology when overexpressed in rat primary hippocampal neurons.
RESULTS: Clinically, all three individuals harboring these mutations had global developmental delays and ID. In our in vitro assay, c.1527G > A and c.2497delG both result in proteins that lack most of the SHANK3a C-terminus and accumulate in the nucleus of transfected cells. Cells expressing these mutants exhibit converging morphological phenotypes including reduced complexity of the dendritic tree, less spines, and less excitatory, but not inhibitory synapses. In contrast, the truncated protein based on c.5008A > T, which lacks only a short part of the sterile alpha motif (SAM) domain in the very SHANK3a C-terminus, does not accumulate in the nucleus and has minor effects on neuronal morphology.
CONCLUSIONS: In spite of the prevalence of SHANK3 disruptions in ASD and ID, only a few human mutations have been functionally characterized; here we characterize three additional mutations. Considering the transcriptional and functional complexity of SHANK3 in healthy neurons, we propose that any heterozygous stop mutation in SHANK3 will lead to a dysequilibrium of SHANK3 isoform expression and alterations in the stoichiometry of SHANK3 protein complexes, resulting in a distinct perturbation of neuronal morphology. This could explain why the clinical phenotype in all three individuals included in this study remains quite severe - regardless of whether there are disruptions in one or more SHANK3 interaction domains.

PMID: 26045941 [PubMed]

Identifying novel interventional strategies for psychiatric disorders: integrating genomics, 'enviromics' and gene-environment interactions in valid preclinical models.

June 6, 2015 - 7:23am
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Identifying novel interventional strategies for psychiatric disorders: integrating genomics, 'enviromics' and gene-environment interactions in valid preclinical models.

Br J Pharmacol. 2014 Oct;171(20):4719-28

Authors: McOmish CE, Burrows EL, Hannan AJ

Abstract
Psychiatric disorders affect a substantial proportion of the population worldwide. This high prevalence, combined with the chronicity of the disorders and the major social and economic impacts, creates a significant burden. As a result, an important priority is the development of novel and effective interventional strategies for reducing incidence rates and improving outcomes. This review explores the progress that has been made to date in establishing valid animal models of psychiatric disorders, while beginning to unravel the complex factors that may be contributing to the limitations of current methodological approaches. We propose some approaches for optimizing the validity of animal models and developing effective interventions. We use schizophrenia and autism spectrum disorders as examples of disorders for which development of valid preclinical models, and fully effective therapeutics, have proven particularly challenging. However, the conclusions have relevance to various other psychiatric conditions, including depression, anxiety and bipolar disorders. We address the key aspects of construct, face and predictive validity in animal models, incorporating genetic and environmental factors. Our understanding of psychiatric disorders is accelerating exponentially, revealing extraordinary levels of genetic complexity, heterogeneity and pleiotropy. The environmental factors contributing to individual, and multiple, disorders also exhibit breathtaking complexity, requiring systematic analysis to experimentally explore the environmental mediators and modulators which constitute the 'envirome' of each psychiatric disorder. Ultimately, genetic and environmental factors need to be integrated via animal models incorporating the spatiotemporal complexity of gene-environment interactions and experience-dependent plasticity, thus better recapitulating the dynamic nature of brain development, function and dysfunction.

PMID: 24846457 [PubMed - indexed for MEDLINE]

The developmental pattern of the RAS/RAF/Erk1/2 pathway in the BTBR autism mouse model.

June 6, 2015 - 7:23am
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The developmental pattern of the RAS/RAF/Erk1/2 pathway in the BTBR autism mouse model.

Int J Dev Neurosci. 2014 Dec;39:2-8

Authors: Yin A, Qiu Y, Jia B, Song T, Yu Y, Alberts I, Zhong M

Abstract
BTBR mice exhibit several autistic-like behaviors and are currently used as a model for understanding mechanisms that may be responsible for the pathogenesis of autism. Ras/Raf/ERK1/2 signaling has been suggested to play an important role in neural development, learning, memory, and cognition. Two studies reported that a deletion of a locus on chromosome 16 containing the mitogen-activated protein kinase 3 (MAPK3) gene, which encodes ERK1, is associated with autism. In the present study, Ras/Raf/ERK1/2 signaling was found to be up-regulated in BTBR mice relative to matched control B6 mice, to further suggest involvement in the pathogenesis of autism. To further characterize the developmental pattern of Ras/Raf/ERK1/2 signaling, varying stages during development were sampled to reveal an up-regulation in newborn and 2-week old BTBR mice relative to age-matched B6 mice. By the age of 3-week, Ras/Raf/ERK1/2 signaling in the brain of BTBR mice was unaltered relative to B6 mice, with this trend maintained in 6-week samples. These results suggest that the alteration of Ras/Raf/ERK signaling in the early developmental stages in mice could contribute to the noted autistic phenotype. Furthermore, these findings support the value of BTBR mice to serve as a human analog for autistic etiological research and aid in a better understanding of the developmental mechanisms of autism.

PMID: 24631207 [PubMed - indexed for MEDLINE]

The implications of de novo coding mutations in simplex autism families.

June 5, 2015 - 6:12am
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The implications of de novo coding mutations in simplex autism families.

Clin Genet. 2015 May;87(5):428-9

Authors: Utami KH

PMID: 25753786 [PubMed - indexed for MEDLINE]

Decoding the molecular evolution of human cognition using comparative genomics.

June 5, 2015 - 6:12am
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Decoding the molecular evolution of human cognition using comparative genomics.

Brain Behav Evol. 2014;84(2):103-16

Authors: Usui N, Co M, Konopka G

Abstract
Identification of genetic and molecular factors responsible for the specialized cognitive abilities of humans is expected to provide important insights into the mechanisms responsible for disorders of cognition such as autism, schizophrenia and Alzheimer's disease. Here, we discuss the use of comparative genomics for identifying salient genes and gene networks that may underlie cognition. We focus on the comparison of human and non-human primate brain gene expression and the utility of building gene coexpression networks for prioritizing hundreds of genes that differ in expression among the species queried. We also discuss the importance of and methods for functional studies of the individual genes identified. Together, this integration of comparative genomics with cellular and animal models should provide improved systems for developing effective therapeutics for disorders of cognition.

PMID: 25247723 [PubMed - indexed for MEDLINE]

Does parent of origin matter? Methylation studies should be performed on patients with multiple copies of the Prader-Willi/Angelman syndrome critical region.

June 5, 2015 - 6:12am
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Does parent of origin matter? Methylation studies should be performed on patients with multiple copies of the Prader-Willi/Angelman syndrome critical region.

Am J Med Genet A. 2014 Oct;164A(10):2514-20

Authors: Aypar U, Brodersen PR, Lundquist PA, Dawson DB, Thorland EC, Hoppman N

Abstract
Deletion of 15q11.2-q13 results in either Prader-Willi syndrome (PWS) or Angelman syndrome (AS) depending on the parent of origin. Duplication of the PWS/AS critical region (PWASCR) has also been reported in association with developmental delay and autism, and it has been shown that they also show a parent-of-origin effect. It is generally accepted that maternal duplications are pathogenic. However, there is conflicting evidence as to the pathogenicity of paternal duplications. We have identified 35 patients with gain of the PWASCR using array comparative genomic hybridization. Methylation testing was performed to determine parent of origin of the extra copies. Of the 35 cases, 22 had a supernumerary marker chromosome 15 (SMC15), 12 had a tandem duplication, and 1 had a tandem triplication. Only one patient had a paternal duplication; this patient does not have features typical of patients with maternal duplication of the PWASCR. Three of the mothers had a tandem duplication (two were paternal and one was maternal origin). While one of the two mothers with paternal duplication was noted not to have autism, the other was noted to have learning disability and depression. Based on our data, we conclude that SMC15 are almost exclusively maternal in origin and result in an abnormal phenotype. Tandem duplications/triplications are generally of maternal origin when ascertained on the basis of abnormal phenotype; however, tandem duplications of paternal origin have also been identified. Therefore, we suggest that methylation testing be performed for cases of tandem duplications/triplications since the pathogenicity of paternal gains is uncertain.

PMID: 24975781 [PubMed - indexed for MEDLINE]

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