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Searching for a minimal set of behaviors for autism detection through feature selection-based machine learning.

January 21, 2016 - 7:24am
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Searching for a minimal set of behaviors for autism detection through feature selection-based machine learning.

Transl Psychiatry. 2015;5:e514

Authors: Kosmicki JA, Sochat V, Duda M, Wall DP

Abstract
Although the prevalence of autism spectrum disorder (ASD) has risen sharply in the last few years reaching 1 in 68, the average age of diagnosis in the United States remains close to 4--well past the developmental window when early intervention has the largest gains. This emphasizes the importance of developing accurate methods to detect risk faster than the current standards of care. In the present study, we used machine learning to evaluate one of the best and most widely used instruments for clinical assessment of ASD, the Autism Diagnostic Observation Schedule (ADOS) to test whether only a subset of behaviors can differentiate between children on and off the autism spectrum. ADOS relies on behavioral observation in a clinical setting and consists of four modules, with module 2 reserved for individuals with some vocabulary and module 3 for higher levels of cognitive functioning. We ran eight machine learning algorithms using stepwise backward feature selection on score sheets from modules 2 and 3 from 4540 individuals. We found that 9 of the 28 behaviors captured by items from module 2, and 12 of the 28 behaviors captured by module 3 are sufficient to detect ASD risk with 98.27% and 97.66% accuracy, respectively. A greater than 55% reduction in the number of behaviorals with negligible loss of accuracy across both modules suggests a role for computational and statistical methods to streamline ASD risk detection and screening. These results may help enable development of mobile and parent-directed methods for preliminary risk evaluation and/or clinical triage that reach a larger percentage of the population and help to lower the average age of detection and diagnosis.

PMID: 25710120 [PubMed - indexed for MEDLINE]

Functional roles of alternative splicing factors in human disease.

January 21, 2016 - 7:24am
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Functional roles of alternative splicing factors in human disease.

Wiley Interdiscip Rev RNA. 2015 May-Jun;6(3):311-26

Authors: Cieply B, Carstens RP

Abstract
Alternative splicing (AS) is an important mechanism used to generate greater transcriptomic and proteomic diversity from a finite genome. Nearly all human gene transcripts are alternatively spliced and can produce protein isoforms with divergent and even antagonistic properties that impact cell functions. Many AS events are tightly regulated in a cell-type or tissue-specific manner, and at different developmental stages. AS is regulated by RNA-binding proteins, including cell- or tissue-specific splicing factors. In the past few years, technological advances have defined genome-wide programs of AS regulated by increasing numbers of splicing factors. These splicing regulatory networks (SRNs) consist of transcripts that encode proteins that function in coordinated and related processes that impact the development and phenotypes of different cell types. As such, it is increasingly recognized that disruption of normal programs of splicing regulated by different splicing factors can lead to human diseases. We will summarize examples of diseases in which altered expression or function of splicing regulatory proteins has been implicated in human disease pathophysiology. As the role of AS continues to be unveiled in human disease and disease risk, it is hoped that further investigations into the functions of numerous splicing factors and their regulated targets will enable the development of novel therapies that are directed at specific AS events as well as the biological pathways they impact.

PMID: 25630614 [PubMed - indexed for MEDLINE]

The roles of CC2D1A and HTR1A gene expressions in autism spectrum disorders.

January 20, 2016 - 7:22am

The roles of CC2D1A and HTR1A gene expressions in autism spectrum disorders.

Metab Brain Dis. 2016 Jan 19;

Authors: Sener EF, Cıkılı Uytun M, Korkmaz Bayramov K, Zararsiz G, Oztop DB, Canatan H, Ozkul Y

Abstract
Classical autism belongs to a group of heterogeneous disorders known as autism spectrum disorders (ASD). Autism is defined as a neurodevelopmental disorder, characterized by repetitive stereotypic behaviors or restricted interests, social withdrawal, and communication deficits. Numerous susceptibility genes and chromosomal abnormalities have been reported in association with autism but the etiology of this disorder is unknown in many cases. CC2D1A gene has been linked to mental retardation (MR) in a family with a large deletion before. Intellectual disability (ID) is a common feature of autistic cases. Therefore we aimed to investigate the expressions of CC2D1A and HTR1A genes with the diagnosis of autism in Turkey. Forty-four autistic patients (35 boys, 9 girls) and 27 controls were enrolled and obtained whole blood samples to isolate RNA samples from each participant. CC2D1A and HTR1A gene expressions were assessed by quantitative Real-Time PCR (qRT-PCR) in Genome and Stem Cell Center, Erciyes University. Both expressions of CC2D1A and HTR1A genes studied on ASD cases and controls were significantly different (p < 0.001). The expression of HTR1A was undetectable in the ASD samples. Comparison of ID and CC2D1A gene expression was also found statistically significant (p = 0.028). CC2D1A gene expression may be used as a candidate gene for ASD cases with ID. Further studies are needed to investigate the potential roles of these CC2D1A and HTR1A genes in their related pathways in ASD.

PMID: 26782176 [PubMed - as supplied by publisher]

Annual Research Review: The role of the environment in the developmental psychopathology of autism spectrum condition.

January 20, 2016 - 7:22am

Annual Research Review: The role of the environment in the developmental psychopathology of autism spectrum condition.

J Child Psychol Psychiatry. 2016 Jan 19;

Authors: Mandy W, Lai MC

Abstract
BACKGROUND: Although autism spectrum condition (ASC) is strongly genetic in origin, accumulating evidence points to the critical roles of various environmental influences on its emergence and subsequent developmental course.
METHODS: A developmental psychopathology framework was used to synthesise literature on environmental factors associated with the onset and course of ASC (based on a systematic search of the literature using PubMed, PsychInfo and Google Scholar databases). Particular emphasis was placed on gene-environment interplay, including gene-environment interaction (G × E) and gene-environment correlation (rGE).
RESULTS: Before conception, advanced paternal and maternal ages may independently enhance offspring risk for ASC. Exogenous prenatal risks are evident (e.g. valproate and toxic chemicals) or possible (e.g. selective serotonin reuptake inhibitors), and processes endogenous to the materno-foeto-placental unit (e.g. maternal diabetes, enhanced steroidogenic activities and maternal immune activation) likely heighten offspring vulnerability to ASC. Folate intake is a prenatal protective factor, with a particular window of action around 4 weeks preconception and during the first trimester. These prenatal risks and protective mechanisms appear to involve G × E and potentially rGE. A variety of perinatal risks are related to offspring ASC risk, possibly reflecting rGE. Postnatal social factors (e.g. caregiver-infant interaction, severe early deprivation) during the first years of life may operate through rGE to influence the likelihood of manifesting a full ASC phenotype from a 'prodromal' phase (a proposal distinct to the discredited and harmful 'refrigerator mother hypothesis'); and later postnatal risks, after the full manifestation of ASC, shape life span development through transactions mediated by rGE. There is no evidence that vaccination is a postnatal risk for ASC.
CONCLUSIONS: Future investigations should consider the specificity of risks for ASC versus other atypical neurodevelopmental trajectories, timing of risk and protective mechanisms, animal model systems to study mechanisms underlying gene-environment interplay, large-sample genome-envirome designs to address G × E and longitudinal studies to elucidate how rGE plays out over time. Clinical and public health implications are discussed.

PMID: 26782158 [PubMed - as supplied by publisher]

Sexual divergence in microtubule function: the novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory.

January 20, 2016 - 7:22am

Sexual divergence in microtubule function: the novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory.

Mol Psychiatry. 2016 Jan 19;

Authors: Amram N, Hacohen-Kleiman G, Sragovich S, Malishkevich A, Katz J, Touloumi O, Lagoudaki R, Grigoriadis NC, Giladi E, Yeheskel A, Pasmanik-Chor M, Jouroukhin Y, Gozes I

Abstract
Activity-dependent neuroprotective protein (ADNP), essential for brain formation, is a frequent autism spectrum disorder (ASD)-mutated gene. ADNP associates with microtubule end-binding proteins (EBs) through its SxIP motif, to regulate dendritic spine formation and brain plasticity. Here, we reveal SKIP, a novel four-amino-acid peptide representing an EB-binding site, as a replacement therapy in an outbred Adnp-deficient mouse model. We discovered, for the first time, axonal transport deficits in Adnp(+/-) mice (measured by manganese-enhanced magnetic resonance imaging), with significant male-female differences. RNA sequencing evaluations showed major age, sex and genotype differences. Function enrichment and focus on major gene expression changes further implicated channel/transporter function and the cytoskeleton. In particular, a significant maturation change (1 month-five months) was observed in beta1 tubulin (Tubb1) mRNA, only in Adnp(+/+) males, and sex-dependent increase in calcium channel mRNA (Cacna1e) in Adnp(+/+) males compared with females. At the protein level, the Adnp(+/-) mice exhibited impaired hippocampal expression of the calcium channel (voltage-dependent calcium channel, Cacnb1) as well as other key ASD-linked genes including the serotonin transporter (Slc6a4), and the autophagy regulator, BECN1 (Beclin1), in a sex-dependent manner. Intranasal SKIP treatment normalized social memory in 8- to 9-month-old Adnp(+/-)-treated mice to placebo-control levels, while protecting axonal transport and ameliorating changes in ASD-like gene expression. The control, all d-amino analog D-SKIP, did not mimic SKIP activity. SKIP presents a novel prototype for potential ASD drug development, a prevalent unmet medical need.Molecular Psychiatry advance online publication, 19 January 2016; doi:10.1038/mp.2015.208.

PMID: 26782054 [PubMed - as supplied by publisher]

Developmental neurogenetics and multimodal neuroimaging of sex differences in autism.

January 20, 2016 - 7:22am

Developmental neurogenetics and multimodal neuroimaging of sex differences in autism.

Brain Imaging Behav. 2016 Jan 19;

Authors: Chen C, Van Horn JD, GENDAAR Research Consortium

Abstract
Examining sex differences in the brain has been historically contentious but is nonetheless important for advancing mental health for both girls and boys. Unfortunately, females in biomedical research remain underrepresented in most mental health conditions including autism spectrum disorders (ASD), even though equal inclusion of females would improve treatment for girls and yield benefits to boys. This review examines sex differences in the relationship between neuroanatomy and neurogenetics of ASD. Recent findings reveal that girls diagnosed with ASD exhibit more intellectual and behavioral problems compared to their male counterparts, suggesting that girls may be less likely diagnosed in the absence of such problems or that they require a higher mutational load to meet the diagnostic criteria. Thus far, the female biased effect of chromosome 4, 5p15.33, 8p, 9p24.1, 11p12-13, 15q, and Xp22.3 and the male biased effect of 1p31.3, 5q12.3, 7q, 9q33.3, 11q13.4, 13q33.3, 16p11.2, 17q11-21, Xp22.33/Yp11.31, DRD1, NLGN3, MAOA, and SHANK1 deletion have been discovered in ASD. The SNPs of genes such as RYR2, UPP2, and the androgen receptor gene have been shown to have sex-biasing factors in both girls and boys diagnosed with ASD. These sex-related genetic factors may drive sex differences in the neuroanatomy of these girls and boys, including abnormal enlargement in temporal gray and white matter volumes, and atypical reduction in cerebellar gray matter volumes and corpus callosum fibers projecting to the anterior frontal cortex in ASD girls relative to boys. Such factors may also be responsible for the attenuation of brain sexual differentiation in adult men and women with ASD; however, much remains to be uncovered or replicated. Future research should leverage further the association between neuroanatomy and genetics in girls for an integrated and interdisciplinary understanding of ASD.

PMID: 26781567 [PubMed - as supplied by publisher]

The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder.

January 20, 2016 - 7:22am

The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder.

Sci Rep. 2016;6:19372

Authors: Wenger TL, Kao C, McDonald-McGinn DM, Zackai EH, Bailey A, Schultz RT, Morrow BE, Emanuel BS, Hakonarson H

Abstract
While abnormal signaling mediated through metabotropic glutamate receptor 5 (mGluR5) is involved in the pathophysiology of Autism Spectrum Disorder (ASD), Fragile X Syndrome and Tuberous Sclerosis, the role of other mGluRs and their associated signaling network genes in syndromic ASD is unknown. This study sought to determine whether mGluR Copy Number Variants (CNV's) were overrepresented in children with syndromic ASD and if mGluR "second hit" confers additional risk for ASD in 22q11.2 Deletion Syndrome (22q11DS). To determine whether mGluR network CNV'S are enriched in syndromic ASD, we examined microarrays from children with ASD (n = 539). Patient categorization (syndromic vs nonsyndromic) was done via blinded medical chart review in mGluR positive and randomly selected mGluR negative cases. 11.5% of ASD had mGluR CNV's vs. 3.2% in controls (p < 0.001). Syndromic ASD was more prevalent in children with mGluR CNVs (74% vs 16%, p < 0.001). A comparison cohort with 22q11DS (n = 25 with ASD, n = 50 without ASD), all haploinsufficient for mGluR network gene RANBP1, were evaluated for "second mGluR hits". 20% with 22q11.2DS + ASD had "second hits" in mGluR network genes vs 2% in 22q11.2DS-ASD (p < 0.014). We propose that altered RANBP1 expression may provide a mechanistic link for several seemingly unrelated genetic and environmental forms of ASD.

PMID: 26781481 [PubMed - in process]

Full UPF3B function is critical for neuronal differentiation of neural stem cells.

January 20, 2016 - 7:22am
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Full UPF3B function is critical for neuronal differentiation of neural stem cells.

Mol Brain. 2015;8:33

Authors: Alrahbeni T, Sartor F, Anderson J, Miedzybrodzka Z, McCaig C, Müller B

Abstract
BACKGROUND: Mutation in the UPF3B gene on chromosome X is implicated in neurodevelopmental disorders including X-linked intellectual disability, autism and schizophrenia. The protein UPF3B is involved in the nonsense-mediated mRNA decay pathway (NMD) that controls mRNA stability and functions in the prevention of the synthesis of truncated proteins.
RESULTS: Here we show that NMD pathway components UPF3B and UPF1 are down-regulated during differentiation of neural stem cells into neurons. Using tethered function assays we found that UPF3B missense mutations described in families with neurodevelopmental disorders reduced the activity of UPF3B protein in NMD. In neural stem cells, UPF3B protein was detected in the cytoplasm and in the nucleus. Similarly in neurons, UPF3B protein was detected in neurites, the somatic cytoplasm and in the nucleus. In both cell types nuclear UPF3B protein was enriched in the nucleolus. Using GFP tagged UPF3B proteins we found that the missense mutations did not affect the cellular localisation. Expression of missense mutant UPF3B disturbed neuronal differentiation and reduced the complexity of the branching of neurites. Neuronal differentiation was similarly affected in the presence of the NMD inhibitor Amlexanox. The expression of mutant UPF3B proteins lead to a subtle increase in mRNA levels of selected NMD targets.
CONCLUSIONS: Together our findings indicate that, despite the down-regulation of NMD factors, functional NMD is critical for neuronal differentiation. We propose that the neurodevelopmental phenotype of UPF3B missense mutation is caused by impairment of NMD function altering neuronal differentiation.

PMID: 26012578 [PubMed - indexed for MEDLINE]

ZNF804A Transcriptional Networks in Differentiating Neurons Derived from Induced Pluripotent Stem Cells of Human Origin.

January 20, 2016 - 7:22am
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ZNF804A Transcriptional Networks in Differentiating Neurons Derived from Induced Pluripotent Stem Cells of Human Origin.

PLoS One. 2015;10(4):e0124597

Authors: Chen J, Lin M, Hrabovsky A, Pedrosa E, Dean J, Jain S, Zheng D, Lachman HM

Abstract
ZNF804A (Zinc Finger Protein 804A) has been identified as a candidate gene for schizophrenia (SZ), autism spectrum disorders (ASD), and bipolar disorder (BD) in replicated genome wide association studies (GWAS) and by copy number variation (CNV) analysis. Although its function has not been well-characterized, ZNF804A contains a C2H2-type zinc-finger domain, suggesting that it has DNA binding properties, and consequently, a role in regulating gene expression. To further explore the role of ZNF804A on gene expression and its downstream targets, we used a gene knockdown (KD) approach to reduce its expression in neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs). KD was accomplished by RNA interference (RNAi) using lentiviral particles containing shRNAs that target ZNF804A mRNA. Stable transduced NPC lines were generated after puromycin selection. A control cell line expressing a random (scrambled) shRNA was also generated. Neuronal differentiation was induced, RNA was harvested after 14 days and transcriptome analysis was carried out using RNA-seq. 1815 genes were found to be differentially expressed at a nominally significant level (p<0.05); 809 decreased in expression in the KD samples, while 1106 increased. Of these, 370 achieved genome wide significance (FDR<0.05); 125 were lower in the KD samples, 245 were higher. Pathway analysis showed that genes involved in interferon-signaling were enriched among those that were down-regulated in the KD samples. Correspondingly, ZNF804A KD was found to affect interferon-alpha 2 (IFNA2)-mediated gene expression. The findings suggest that ZNF804A may affect a differentiating neuron's response to inflammatory cytokines, which is consistent with models of SZ and ASD that support a role for infectious disease, and/or autoimmunity in a subgroup of patients.

PMID: 25905630 [PubMed - indexed for MEDLINE]

Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour.

January 20, 2016 - 7:22am
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Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour.

Mol Psychiatry. 2015 May;20(5):632-9

Authors: Bacon C, Schneider M, Le Magueresse C, Froehlich H, Sticht C, Gluch C, Monyer H, Rappold GA

Abstract
Neurodevelopmental disorders are multi-faceted and can lead to intellectual disability, autism spectrum disorder and language impairment. Mutations in the Forkhead box FOXP1 gene have been linked to all these disorders, suggesting that it may play a central role in various cognitive and social processes. To understand the role of Foxp1 in the context of neurodevelopment leading to alterations in cognition and behaviour, we generated mice with a brain-specific Foxp1 deletion (Nestin-Cre(Foxp1-/-)mice). The mutant mice were viable and allowed for the first time the analysis of pre- and postnatal neurodevelopmental phenotypes, which included a pronounced disruption of the developing striatum and more subtle alterations in the hippocampus. More detailed analysis in the CA1 region revealed abnormal neuronal morphogenesis that was associated with reduced excitability and an imbalance of excitatory to inhibitory input in CA1 hippocampal neurons in Nestin-Cre(Foxp1-/-) mice. Foxp1 ablation was also associated with various cognitive and social deficits, providing new insights into its behavioural importance.

PMID: 25266127 [PubMed - indexed for MEDLINE]

The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis.

January 20, 2016 - 7:22am
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The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis.

Mol Psychiatry. 2015 May;20(5):640-6

Authors: LoParo D, Waldman ID

Abstract
The oxytocin receptor gene (OXTR) has been studied as a risk factor for autism spectrum disorder (ASD) owing to converging evidence from multiple levels of analysis that oxytocin (OXT) has an important role in the regulation of affiliative behavior and social bonding in both nonhuman mammals and humans. Inconsistency in the effect sizes of the OXTR variants included in association studies render it unclear whether OXTR is truly associated with ASD, and, if so, which OXTR single-nucleotide polymorphisms (SNPs) are associated. Thus, a meta-analytic review of extant studies is needed to determine whether OXTR shows association with ASD, and to elucidate which specific SNPs have a significant effect on ASD. The current meta-analysis of 16 OXTR SNPs included 3941 individuals with ASD from 11 independent samples, although analyses of each individual SNP included a subset of this total. We found significant associations between ASD and the SNPs rs7632287, rs237887, rs2268491 and rs2254298. OXTR was also significantly associated with ASD in a gene-based test. The current meta-analysis is the largest and most comprehensive investigation of the association of OXTR with ASD and the findings suggest directions for future studies of the etiology of ASD.

PMID: 25092245 [PubMed - indexed for MEDLINE]

Mutational analyses of the FMR1 gene in Chinese pediatric population of fragile x suspects: low tolerance for point mutation.

January 20, 2016 - 7:22am
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Mutational analyses of the FMR1 gene in Chinese pediatric population of fragile x suspects: low tolerance for point mutation.

J Child Neurol. 2015 May;30(6):803-6

Authors: Luo S, Huang W, Xia Q, Du Q, Wu L, Duan R

Abstract
CGG repeat expansion is the most common cause of fragile X syndrome. Numerous efforts have been made to identify novel mutations in patients with intellectual disability, developmental delay, and/or autism. To evaluate the mutational spectrum in the at-risk Chinese population, 60 pediatric patients presenting fragile X traits but normal-sized CGG repeats were sequenced for all 17 exons and regulatory regions in FMR1. A c.879A>C mutation, reported to alter a neighboring splicing, was detected in a severely retarded male and his normal mother. However, the exon junction appears unaffected. A 237-kb deletion covering the entire FMR1 was identified to cause moderate intellectual disability and marked hyperactivity in an 8-year-old boy. The 5' and 3' breakpoints were buried in the surrounding long interspersed and short interspersed elements, respectively. In general, missense mutations do not commonly cause fragile X syndrome, whereas deletions should be considered with caution in patient referrals presenting with developmental delay and/or ordinary retardation.

PMID: 24963073 [PubMed - indexed for MEDLINE]

Recurrent copy number variations as risk factors for Autism Spectrum Disorders: analysis of the clinical implications.

January 19, 2016 - 7:09am

Recurrent copy number variations as risk factors for Autism Spectrum Disorders: analysis of the clinical implications.

Clin Genet. 2016 Jan 18;

Authors: Oikonomakis V, Kosma K, Mitrakos A, Sofocleous C, Pervanidou P, Syrmou A, Pampanos A, Psoni S, Fryssira H, Kanavakis E, Kitsiou-Tzeli S, Tzetis M

Abstract
Chromosomal Microarray Analysis (CMA) is currently considered a first tier diagnostic assay for the investigation of Autism Spectrum Disorders (ASD), developmental delay (DD) and intellectual disability (ID) of unknown etiology. High resolution arrays were utilized for the identification of Copy Number Variations (CNVs) in 195 ASD patients of Greek origin (126 males, 69 females). CMA resulted in the detection of 65 CNVs, excluding the known polymorphic CNPs also found in the database of genomic variants (DGV), for 51/195 patients (26.1%). Parental DNA testing in 20/51 patients revealed that 17 CNVs were de novo, 6 paternal and 3 of maternal origin. The majority of the 65 CNVs were deletions (66.1%), of which 5 on the X-chromosome while the duplications, of which 7 on the X-chromosome, were rarer (22/65, 33.8%). Fifty-one CNVs from a total of 65, reported for our cohort of ASD patients, were of diagnostic significance and well described in the literature while 14 CNVs (8 losses, 6 gains) were characterized as Variants of Unknown Significance (VOUS) and need further investigation. Amongst the 51 patients 39 carried one CNV, 10 carried two CNVs and 2 carried three CNVs. The use of CMA, its clinical validity and utility was assessed.

PMID: 26777411 [PubMed - as supplied by publisher]

Executive functioning deficits in children with neurofibromatosis type 1: The influence of intellectual and social functioning.

January 17, 2016 - 7:05am

Executive functioning deficits in children with neurofibromatosis type 1: The influence of intellectual and social functioning.

Am J Med Genet B Neuropsychiatr Genet. 2016 Jan 15;

Authors: Plasschaert E, Van Eylen L, Descheemaeker MJ, Noens I, Legius E, Steyaert J

Abstract
The aim of this study was to provide a broad picture of Executive Functioning (EF) in NF1 children, while taking into account their lower average IQ and increased Autism Spectrum Disorder (ASD) symptoms. This was done by administering an extended battery of tasks and questionnaires, designed to reduce task impurity, that measures five EF domains (inhibition, cognitive flexibility, working memory, generativity and planning) in a laboratory setting and in daily life. Data are presented for 42 age- and gender-matched NF1, 52 typically developing, and 52 ASD children (8-18 years). Our results indicated that although EF is highly influenced by IQ and severity of ASD symptoms, EF deficits seem to be a core feature of NF1 and not merely a secondary effect of a lower IQ and/or increased ASD symptoms. However, additional research is needed to confirm these findings. © 2016 Wiley Periodicals, Inc.

PMID: 26773288 [PubMed - as supplied by publisher]

A genomic view on epilepsy and autism candidate genes.

January 17, 2016 - 7:05am

A genomic view on epilepsy and autism candidate genes.

Genomics. 2016 Jan 6;

Authors: Jabbari K, Nürnberg P

Abstract
Epilepsy is a common complex disorder most frequently associated with psychiatric and neurological diseases. Massive parallel sequencing of individual or cohort genomes and exomes led the identification of several disease associated genes. We review here the candidate genes in epilepsy genetics with focus on exome and gene panel data. Together with the examination of brain expressed genes and post synaptic proteome the results show that: (1) Non-metabolic epilepsies and autism candidate genes tend to be AT-rich and (2) large transcript size and local AT-richness are characteristic features of genes involved in developmental brain disorders and synaptic functions. These results point to the preferential location of core epilepsy and autism candidate genes in late replicating, GC-poor chromosomal regions (isochores). These results indicate that the genomic alterations leading to some brain disorders are confined to responsive chromatin areas harboring brain critical genes.

PMID: 26772991 [PubMed - as supplied by publisher]

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

January 16, 2016 - 7:04am

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

Cell. 2016 Jan 14;164(1-2):183-196

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

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

PMID: 26771491 [PubMed - as supplied by publisher]

Nutritional and Metabolic Biomarkers in Autism Spectrum Disorders: An Exploratory Study.

January 16, 2016 - 7:04am
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Nutritional and Metabolic Biomarkers in Autism Spectrum Disorders: An Exploratory Study.

Integr Med (Encinitas). 2015 Apr;14(2):40-53

Authors: Esparham AE, Smith T, Belmont JM, Haden M, Wagner LE, Evans RG, Drisko JA

Abstract
CONTEXT: Autism spectrum disorder (ASD) is currently on the rise, now affecting approximately 1 in 68 children in the United States according to a 2010 surveillance summary from the Centers for Disease Control and Prevention (CDC). This figure is an estimated increase of 78% from the figure in 2002. The CDC suggests that more investigation is needed to understand this astounding increase in autism in such a short period.
OBJECTIVE: The aim of this pilot study was to determine whether a group of children with ASD exhibited similar variations in a broad array of potential correlates, including medical histories, symptoms, genetics, and multiple nutritional and metabolic biomarkers.
DESIGN: This study was a retrospective, descriptive chart review.
SETTING: The study took place at the University of Kansas Medical Center (KUMC).
PARTICIPANTS: Participants were 7 children with ASD who had sought treatment at the Integrative Medicine Clinic at the medical center.
RESULTS: A majority of the children exhibited an elevated copper:zinc ratio and abnormal vitamin D levels. Children also demonstrated abnormal levels of the essential fatty acids: (1) α-linolenic acid (ALA)- C13:3W3, and (2) linoleic acid (LA)-C18:2W6; high levels of docosahexaenoic acid (DHA); and an elevated ω-6:ω-3 ratio. Three of 7 children demonstrated abnormal manganese levels. Children did not demonstrate elevated urine pyruvate or lactate but did have abnormal detoxification markers. Three of 7 patients demonstrated abnormalities in citric acid metabolites, bacterial metabolism, and fatty acid oxidation markers. A majority demonstrated elevated serum immunoglobulin G (IgG) antibodies to casein, egg whites, egg yolks, and peanuts. A majority had absent glutathione S-transferase (GSTM) at the 1p13.3 location, and 3 of 7 children were heterozygous for the glutathione S-transferase I105V (GSTP1). A majority also exhibited genetic polymorphism of the mitochondrial gene superoxide dismutase A16V (SOD2).
CONCLUSIONS: The findings from this small group of children with ASD points to the existence of nutritional, metabolic, and genetic correlates of ASD. These factors appear to be important potential abnormalities that warrant a case control study to evaluate their reliability and validity as markers of ASD.

PMID: 26770138 [PubMed]

A specific mutation in TBL1XR1 causes Pierpont syndrome.

January 16, 2016 - 7:04am
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A specific mutation in TBL1XR1 causes Pierpont syndrome.

J Med Genet. 2016 Jan 14;

Authors: Heinen CA, Jongejan A, Watson PJ, Redeker B, Boelen A, Boudzovitch-Surovtseva O, Forzano F, Hordijk R, Kelley R, Olney AH, Pierpont ME, Schaefer GB, Stewart F, van Trotsenburg AS, Fliers E, Schwabe JW, Hennekam RC

Abstract
BACKGROUND: The combination of developmental delay, facial characteristics, hearing loss and abnormal fat distribution in the distal limbs is known as Pierpont syndrome. The aim of the present study was to detect and study the cause of Pierpont syndrome.
METHODS: We used whole-exome sequencing to analyse four unrelated individuals with Pierpont syndrome, and Sanger sequencing in two other unrelated affected individuals. Expression of mRNA of the wild-type candidate gene was analysed in human postmortem brain specimens, adipose tissue, muscle and liver. Expression of RNA in lymphocytes in patients and controls was additionally analysed. The variant protein was expressed in, and purified from, HEK293 cells to assess its effect on protein folding and function.
RESULTS: We identified a single heterozygous missense variant, c.1337A>C (p.Tyr446Cys), in transducin β-like 1 X-linked receptor 1 (TBL1XR1) as disease-causing in all patients. TBL1XR1 mRNA expression was demonstrated in pituitary, hypothalamus, white and brown adipose tissue, muscle and liver. mRNA expression is lower in lymphocytes of two patients compared with the four controls. The mutant TBL1XR1 protein assembled correctly into the nuclear receptor corepressor (NCoR)/ silencing mediator for retinoid and thyroid receptors (SMRT) complex, suggesting a dominant-negative mechanism. This contrasts with loss-of-function germline TBL1XR1 deletions and other TBL1XR1 mutations that have been implicated in autism. However, autism is not present in individuals with Pierpont syndrome.
CONCLUSIONS: This study identifies a specific TBL1XR1 mutation as the cause of Pierpont syndrome. Deletions and other mutations in TBL1XR1 can cause autism. The marked differences between Pierpont patients with the p.Tyr446Cys mutation and individuals with other mutations and whole gene deletions indicate a specific, but as yet unknown, disease mechanism of the TBL1XR1 p.Tyr446Cys mutation.

PMID: 26769062 [PubMed - as supplied by publisher]

Crystal structure reveals specific recognition of a G-quadruplex RNA by a β-turn in the RGG motif of FMRP.

January 16, 2016 - 7:04am
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Crystal structure reveals specific recognition of a G-quadruplex RNA by a β-turn in the RGG motif of FMRP.

Proc Natl Acad Sci U S A. 2015 Sep 29;112(39):E5391-400

Authors: Vasilyev N, Polonskaia A, Darnell JC, Darnell RB, Patel DJ, Serganov A

Abstract
Fragile X Mental Retardation Protein (FMRP) is a regulatory RNA binding protein that plays a central role in the development of several human disorders including Fragile X Syndrome (FXS) and autism. FMRP uses an arginine-glycine-rich (RGG) motif for specific interactions with guanine (G)-quadruplexes, mRNA elements implicated in the disease-associated regulation of specific mRNAs. Here we report the 2.8-Å crystal structure of the complex between the human FMRP RGG peptide bound to the in vitro selected G-rich RNA. In this model system, the RNA adopts an intramolecular K(+)-stabilized G-quadruplex structure composed of three G-quartets and a mixed tetrad connected to an RNA duplex. The RGG peptide specifically binds to the duplex-quadruplex junction, the mixed tetrad, and the duplex region of the RNA through shape complementarity, cation-π interactions, and multiple hydrogen bonds. Many of these interactions critically depend on a type I β-turn, a secondary structure element whose formation was not previously recognized in the RGG motif of FMRP. RNA mutagenesis and footprinting experiments indicate that interactions of the peptide with the duplex-quadruplex junction and the duplex of RNA are equally important for affinity and specificity of the RGG-RNA complex formation. These results suggest that specific binding of cellular RNAs by FMRP may involve hydrogen bonding with RNA duplexes and that RNA duplex recognition can be a characteristic RNA binding feature for RGG motifs in other proteins.

PMID: 26374839 [PubMed - indexed for MEDLINE]

Genetic variation in CD38 and breastfeeding experience interact to impact infants' attention to social eye cues.

January 16, 2016 - 7:04am
Related Articles

Genetic variation in CD38 and breastfeeding experience interact to impact infants' attention to social eye cues.

Proc Natl Acad Sci U S A. 2015 Sep 29;112(39):E5434-42

Authors: Krol KM, Monakhov M, Lai PS, Ebstein RP, Grossmann T

Abstract
Attending to emotional information conveyed by the eyes is an important social skill in humans. The current study examined this skill in early development by measuring attention to eyes while viewing emotional faces in 7-mo-old infants. In particular, we investigated individual differences in infant attention to eyes in the context of genetic variation (CD38 rs3796863 polymorphism) and experiential variation (exclusive breastfeeding duration) related to the oxytocin system. Our results revealed that, whereas infants at this age show a robust fear bias (increased attention to fearful eyes), their attention to angry and happy eyes varies as a function of exclusive breastfeeding experience and genetic variation in CD38. Specifically, extended exclusive breastfeeding duration selectively enhanced looking preference to happy eyes and decreased looking to angry eyes. Importantly, however, this interaction was impacted by CD38 variation, such that only the looking preferences of infants homozygous for the C allele of rs3796863 were affected by breastfeeding experience. This genotype has been associated with reduced release of oxytocin and higher rates of autism. In contrast, infants with the CA/AA genotype showed similar looking preferences regardless of breastfeeding exposure. Thus, differences in the sensitivity to emotional eyes may be linked to an interaction between the endogenous (CD38) and exogenous (breastfeeding) availability of oxytocin. These findings underline the importance of maternal care and the oxytocin system in contributing to the early development of responding to social eye cues.

PMID: 26371313 [PubMed - indexed for MEDLINE]

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