pubmed: autism and genetics

Subscribe to pubmed: autism and genetics feed pubmed: autism and genetics
NCBI: db=pubmed; Term=autism AND genetics
Updated: 46 min 42 sec ago

MicroRNA-181 promotes synaptogenesis and attenuates axonal outgrowth in cortical neurons.

March 28, 2016 - 8:45am
Related Articles

MicroRNA-181 promotes synaptogenesis and attenuates axonal outgrowth in cortical neurons.

Cell Mol Life Sci. 2016 Mar 26;

Authors: Kos A, Olde Loohuis N, Meinhardt J, van Bokhoven H, Kaplan BB, Martens GJ, Aschrafi A

Abstract
MicroRNAs (miRs) are non-coding gene transcripts abundantly expressed in both the developing and adult mammalian brain. They act as important modulators of complex gene regulatory networks during neuronal development and plasticity. miR-181c is highly abundant in cerebellar cortex and its expression is increased in autism patients as well as in an animal model of autism. To systematically identify putative targets of miR-181c, we repressed this miR in growing cortical neurons and found over 70 differentially expressed target genes using transcriptome profiling. Pathway analysis showed that the miR-181c-modulated genes converge on signaling cascades relevant to neurite and synapse developmental processes. To experimentally examine the significance of these data, we inhibited miR-181c during rat cortical neuronal maturation in vitro; this loss-of miR-181c function resulted in enhanced neurite sprouting and reduced synaptogenesis. Collectively, our findings suggest that miR-181c is a modulator of gene networks associated with cortical neuronal maturation.

PMID: 27017280 [PubMed - as supplied by publisher]

Quantitative profiling of brain lipid raft proteome in a mouse model of fragile X syndrome.

March 28, 2016 - 8:45am
Related Articles

Quantitative profiling of brain lipid raft proteome in a mouse model of fragile X syndrome.

PLoS One. 2015;10(4):e0121464

Authors: Kalinowska M, Castillo C, Francesconi A

Abstract
Fragile X Syndrome, a leading cause of inherited intellectual disability and autism, arises from transcriptional silencing of the FMR1 gene encoding an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). FMRP can regulate the expression of approximately 4% of brain transcripts through its role in regulation of mRNA transport, stability and translation, thus providing a molecular rationale for its potential pleiotropic effects on neuronal and brain circuitry function. Several intracellular signaling pathways are dysregulated in the absence of FMRP suggesting that cellular deficits may be broad and could result in homeostatic changes. Lipid rafts are specialized regions of the plasma membrane, enriched in cholesterol and glycosphingolipids, involved in regulation of intracellular signaling. Among transcripts targeted by FMRP, a subset encodes proteins involved in lipid biosynthesis and homeostasis, dysregulation of which could affect the integrity and function of lipid rafts. Using a quantitative mass spectrometry-based approach we analyzed the lipid raft proteome of Fmr1 knockout mice, an animal model of Fragile X syndrome, and identified candidate proteins that are differentially represented in Fmr1 knockout mice lipid rafts. Furthermore, network analysis of these candidate proteins reveals connectivity between them and predicts functional connectivity with genes encoding components of myelin sheath, axonal processes and growth cones. Our findings provide insight to aid identification of molecular and cellular dysfunctions arising from Fmr1 silencing and for uncovering shared pathologies between Fragile X syndrome and other autism spectrum disorders.

PMID: 25849048 [PubMed - indexed for MEDLINE]

Cerebellar contribution to higher- and lower-order rule learning and cognitive flexibility in mice.

March 26, 2016 - 8:40am

Cerebellar contribution to higher- and lower-order rule learning and cognitive flexibility in mice.

Neuroscience. 2016 Mar 21;

Authors: Dickson PE, Cairns J, Goldowitz D, Mittleman G

Abstract
Cognitive flexibility has traditionally been considered a frontal lobe function. However, converging evidence suggests involvement of a larger brain circuit which includes the cerebellum. Reciprocal pathways connecting the cerebellum to the prefrontal cortex provide a biological substrate through which the cerebellum may modulate higher cognitive functions, and it has been observed that cognitive inflexibility and cerebellar pathology co-occur in psychiatric disorders (e.g., autism, schizophrenia, addiction). However, the degree to which the cerebellum contributes to distinct forms of cognitive flexibility and rule learning is unknown. We tested lurcher↔wildtype aggregation chimeras which lose 0%-100% of cerebellar Purkinje cells during development on a touchscreen-mediated attentional set-shifting task to assess the contribution of the cerebellum to higher- and lower-order rule learning and cognitive flexibility. Purkinje cells, the sole output of the cerebellar cortex, ranged from 0 to 108,390 in tested mice. Reversal learning and extradimensional set-shifting were impaired in mice with ⩾ 95% Purkinje cell loss. Cognitive deficits were unrelated to motor deficits in ataxic mice. Acquisition of a simple visual discrimination and an attentional-set were unrelated to Purkinje cells. A positive relationship was observed between Purkinje cells and errors when exemplars from a novel, non-relevant dimension were introduced. Collectively, these data suggest that the cerebellum contributes to higher-order cognitive flexibility, lower-order cognitive flexibility, and attention to novel stimuli, but not the acquisition of higher- and lower-order rules. These data indicate that the cerebellar pathology observed in psychiatric disorders may underlie deficits involving cognitive flexibility and attention to novel stimuli.

PMID: 27012612 [PubMed - as supplied by publisher]

Autism and chromosome abnormalities - A Review.

March 26, 2016 - 8:40am

Autism and chromosome abnormalities - A Review.

Clin Anat. 2016 Mar 25;

Authors: Bergbaum A, Mackie-Ogilvie C

Abstract
The neuro-behavioral disorder of autism was first described in the 1940s and was predicted to have a biological basis. Since that time, with the growth of genetic investigations particularly in the area of pediatric development, an increasing number of children with autism and related disorders (autistic spectrum disorders, ASD) have been the subject of genetic studies both in the clinical setting and in the wider research environment. However, a full understanding of the biological basis of ASDs has yet to be achieved. Early observations of children with chromosomal abnormalities detected by G-banded chromosome analysis (karyotyping) and in situ hybridization revealed, in some cases, ASD associated with other features arising from such an abnormality. The introduction of higher resolution techniques for whole genome screening, such as array comparative genome hybridization (aCGH), allowed smaller imbalances to be detected, some of which are now considered to represent autism susceptibility loci. In this review, we describe some of the work underpinning the conclusion that ASDs have a genetic basis; a brief history of the developments in genetic analysis tools over the last fifty years; and the most common chromosomal abnormalities found in association with ASDs. Introduction of next generation sequencing (NGS) into the clinical diagnostic setting is likely to provide further insights into this complex field but it will not be covered in this review. This article is protected by copyright. All rights reserved.

PMID: 27012322 [PubMed - as supplied by publisher]

In Pursuit of New Imprinting Syndromes by Epimutation Screening in Idiopathic Neurodevelopmental Disorder Patients.

March 26, 2016 - 8:40am
Related Articles

In Pursuit of New Imprinting Syndromes by Epimutation Screening in Idiopathic Neurodevelopmental Disorder Patients.

Biomed Res Int. 2015;2015:341986

Authors: Mayo S, Monfort S, Roselló M, Oltra S, Orellana C, Martínez F

Abstract
Alterations of epigenetic mechanisms, and more specifically imprinting modifications, could be responsible of neurodevelopmental disorders such as intellectual disability (ID) or autism together with other associated clinical features in many cases. Currently only eight imprinting syndromes are defined in spite of the fact that more than 200 genes are known or predicted to be imprinted. Recent publications point out that some epimutations which cause imprinting disorders may affect simultaneously different imprinted loci, suggesting that DNA-methylation may have been altered more globally. Therefore, we hypothesised that the detection of altered methylation patterns in known imprinting loci will indirectly allow identifying new syndromes due to epimutations among patients with unexplained ID. In a screening for imprinting alterations in 412 patients with syndromic ID/autism we found five patients with altered methylation in the four genes studied: MEG3, H19, KCNQ1OT1, and SNRPN. Remarkably, the cases with partial loss of methylation in KCNQ1OT1 and SNRPN present clinical features different to those associated with the corresponding imprinting syndromes, suggesting a multilocus methylation defect in accordance with our initial hypothesis. Consequently, our results are a proof of concept that the identification of epimutations in known loci in patients with clinical features different from those associated with known syndromes will eventually lead to the definition of new imprinting disorders.

PMID: 26106604 [PubMed - indexed for MEDLINE]

IQSEC2 and X-linked syndromal intellectual disability.

March 25, 2016 - 8:38am

IQSEC2 and X-linked syndromal intellectual disability.

Psychiatr Genet. 2016 Mar 23;

Authors: Alexander-Bloch AF, McDougle CJ, Ullman Z, Sweetser DA

Abstract
Despite the recent acceleration in the discovery of genetic risk factors for intellectual disability (ID), the genetic etiology of ID is unknown in approximately half of cases and remains a major frontier of genetics in medicine and psychiatry. The distinction between syndromal and nonsyndromal forms of ID is of great clinical importance, but the boundary between these clinical entities is difficult to ascertain for many genes of interest. ID is more common in men than in women, but the genetic explanation of this sex asymmetry is incompletely understood. This Review systematically examines the reported cases of X-linked ID caused by de novo loss-of-function mutations in the gene IQSEC2. This gene is largely known as a cause of X-linked nonsyndromal ID in male patients. However, depending on the severity of the mutation, the phenotypic spectrum of IQSEC2-related ID can range from the classic X-linked nonsyndromal form of the disease to a severe syndrome that has been reported in the context of de novo mutations only, in both male and female patients. Bioinformatics analysis suggests that truncation of the longer of the two protein isoforms of the gene can be sufficient to lead to the syndrome, which may be caused by the disruption of cell signaling and signal transduction pathways. The clinical features of the syndrome converge on a pattern of global developmental delay, deficits in social communication, stereotypical hand movements, and hypotonia. In addition, many if not all of these patients have seizures, microcephaly, and language regression in addition to delay. We argue that it is clinically appropriate to test for IQSEC2 mutations in male and female patients with this symptom profile but without a known genetic mutation.

PMID: 27010919 [PubMed - as supplied by publisher]

Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21).

March 25, 2016 - 8:38am

Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21).

Hum Mol Genet. 2016 Mar 22;

Authors: Heon E, Kim G, Qin S, Garrison JE, Tavares E, Vincent A, Nuangchamnong N, Scott CA, Slusarski DC, Sheffield VC

Abstract
Bardet Biedl syndrome (BBS) is a multisystem genetically heterogeneous ciliopathy that most commonly leads to obesity, photoreceptor degeneration, digit anomalies, genito-urinary abnormalities, as well as cognitive impairment with autism, among other features. Sequencing of a DNA sample from a 17 year old female affected with BBS did not identify any mutation in the known BBS genes. Whole genome sequencing identified a novel loss-of-function disease-causing homozygous mutation (K102*) inC8ORF37, a gene coding for a cilia protein. The proband was overweight (BMI 29.1) with a slowly progressive rod-cone dystrophy, a mild learning difficulty, high myopia, 3 limb post-axial polydactyly, horseshoe kidney, abnormally positioned uterus, and elevated liver enzymes. Mutations inC8ORF37were previously associated with severe autosomal recessive retinal dystrophies (retinitis pigmentosa RP64 and cone-rod dystrophy CORD16) but not BBS. To elucidate the functional role ofC8ORF37in a vertebrate system, we performed gene knockdown inDanio rerioand assessed the cardinal features of BBS and visual function. Knockdown ofc8orf37resulted in impaired visual behavior and BBS-related phenotypes, specifically, defects in the formation of Kupffer's vesicle and delays in retrograde transport. Specificity of these phenotypes to BBS knockdown was shown with rescue experiments. Over-expression of human missense mutations in zebrafish also resulted in impaired visual behavior and BBS-related phenotypes. This is the first functional validation and association ofC8ORF37mutations with the BBS phenotype, which identifies BBS21. The zebrafish studies hereby show thatC8ORF37variants underlie clinically diagnosed BBS-related phenotypes as well as isolated retinal degeneration.

PMID: 27008867 [PubMed - as supplied by publisher]

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms.

March 25, 2016 - 8:38am
Related Articles

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms.

Neurotherapeutics. 2015 Jul;12(3):553-71

Authors: Gamsiz ED, Sciarra LN, Maguire AM, Pescosolido MF, van Dyck LI, Morrow EM

Abstract
Autism spectrum disorder (ASD) is a group of highly genetic neurodevelopmental disorders characterized by language, social, cognitive, and behavioral abnormalities. ASD is a complex disorder with a heterogeneous etiology. The genetic architecture of autism is such that a variety of different rare mutations have been discovered, including rare monogenic conditions that involve autistic symptoms. Also, de novo copy number variants and single nucleotide variants contribute to disease susceptibility. Finally, autosomal recessive loci are contributing to our understanding of inherited factors. We will review the progress that the field has made in the discovery of these rare genetic variants in autism. We argue that mutation discovery of this sort offers an important opportunity to identify neurodevelopmental mechanisms in disease. The hope is that these mechanisms will show some degree of convergence that may be amenable to treatment intervention.

PMID: 26105128 [PubMed - indexed for MEDLINE]

Therapeutic Advances in Autism and Other Neurodevelopmental Disorders.

March 25, 2016 - 8:38am
Related Articles

Therapeutic Advances in Autism and Other Neurodevelopmental Disorders.

Neurotherapeutics. 2015 Jul;12(3):519-20

Authors: Neul JL, Sahin M

PMID: 26076992 [PubMed - indexed for MEDLINE]

Angelman Syndrome.

March 25, 2016 - 8:38am
Related Articles

Angelman Syndrome.

Neurotherapeutics. 2015 Jul;12(3):641-50

Authors: Margolis SS, Sell GL, Zbinden MA, Bird LM

Abstract
In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1-2% of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.

PMID: 26040994 [PubMed - indexed for MEDLINE]

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism.

March 25, 2016 - 8:38am
Related Articles

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism.

Neurotherapeutics. 2015 Jul;12(3):521-33

Authors: Ellegood J, Crawley JN

Abstract
In order to understand the consequences of the mutation on behavioral and biological phenotypes relevant to autism, mutations in many of the risk genes for autism spectrum disorder have been experimentally generated in mice. Here, we summarize behavioral outcomes and neuroanatomical abnormalities, with a focus on high-resolution magnetic resonance imaging of postmortem mouse brains. Results are described from multiple mouse models of autism spectrum disorder and comorbid syndromes, including the 15q11-13, 16p11.2, 22q11.2, Cntnap2, Engrailed2, Fragile X, Integrinβ3, MET, Neurexin1a, Neuroligin3, Reelin, Rett, Shank3, Slc6a4, tuberous sclerosis, and Williams syndrome models, and inbred strains with strong autism-relevant behavioral phenotypes, including BTBR and BALB. Concomitant behavioral and neuroanatomical abnormalities can strengthen the interpretation of results from a mouse model, and may elevate the usefulness of the model system for therapeutic discovery.

PMID: 26036957 [PubMed - indexed for MEDLINE]

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back.

March 25, 2016 - 8:38am
Related Articles

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back.

Neurotherapeutics. 2015 Jul;12(3):584-608

Authors: Gross C, Hoffmann A, Bassell GJ, Berry-Kravis EM

Abstract
Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNA-binding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.

PMID: 25986746 [PubMed - indexed for MEDLINE]

Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring.

March 25, 2016 - 8:38am
Related Articles

Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring.

Reprod Biol Endocrinol. 2015;13:35

Authors: Sharma R, Agarwal A, Rohra VK, Assidi M, Abu-Elmagd M, Turki RF

Abstract
Over the last decade, there has been a significant increase in average paternal age when the first child is conceived, either due to increased life expectancy, widespread use of contraception, late marriages and other factors. While the effect of maternal ageing on fertilization and reproduction is well known and several studies have shown that women over 35 years have a higher risk of infertility, pregnancy complications, spontaneous abortion, congenital anomalies, and perinatal complications. The effect of paternal age on semen quality and reproductive function is controversial for several reasons. First, there is no universal definition for advanced paternal ageing. Secondly, the literature is full of studies with conflicting results, especially for the most common parameters tested. Advancing paternal age also has been associated with increased risk of genetic disease. Our exhaustive literature review has demonstrated negative effects on sperm quality and testicular functions with increasing paternal age. Epigenetics changes, DNA mutations along with chromosomal aneuploidies have been associated with increasing paternal age. In addition to increased risk of male infertility, paternal age has also been demonstrated to impact reproductive and fertility outcomes including a decrease in IVF/ICSI success rate and increasing rate of preterm birth. Increasing paternal age has shown to increase the incidence of different types of disorders like autism, schizophrenia, bipolar disorders, and childhood leukemia in the progeny. It is thereby essential to educate the infertile couples on the disturbing links between increased paternal age and rising disorders in their offspring, to better counsel them during their reproductive years.

PMID: 25928123 [PubMed - indexed for MEDLINE]

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder.

March 25, 2016 - 8:38am
Related Articles

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder.

Neurotherapeutics. 2015 Jul;12(3):609-19

Authors: Tilot AK, Frazier TW, Eng C

Abstract
Germline mutations in PTEN, which encodes a widely expressed phosphatase, was mapped to 10q23 and identified as the susceptibility gene for Cowden syndrome, characterized by macrocephaly and high risks of breast, thyroid, and other cancers. The phenotypic spectrum of PTEN mutations expanded to include autism with macrocephaly only 10 years ago. Neurological studies of patients with PTEN-associated autism spectrum disorder (ASD) show increases in cortical white matter and a distinctive cognitive profile, including delayed language development with poor working memory and processing speed. Once a germline PTEN mutation is found, and a diagnosis of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome made, the clinical outlook broadens to include higher lifetime risks for multiple cancers, beginning in childhood with thyroid cancer. First described as a tumor suppressor, PTEN is a major negative regulator of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway-controlling growth, protein synthesis, and proliferation. This canonical function combines with less well-understood mechanisms to influence synaptic plasticity and neuronal cytoarchitecture. Several excellent mouse models of Pten loss or dysfunction link these neural functions to autism-like behavioral abnormalities, such as altered sociability, repetitive behaviors, and phenotypes like anxiety that are often associated with ASD in humans. These models also show the promise of mTOR inhibitors as therapeutic agents capable of reversing phenotypes ranging from overgrowth to low social behavior. Based on these findings, therapeutic options for patients with PTEN hamartoma tumor syndrome and ASD are coming into view, even as new discoveries in PTEN biology add complexity to our understanding of this master regulator.

PMID: 25916396 [PubMed - indexed for MEDLINE]

Phelan-McDermid Syndrome and SHANK3: Implications for Treatment.

March 25, 2016 - 8:38am
Related Articles

Phelan-McDermid Syndrome and SHANK3: Implications for Treatment.

Neurotherapeutics. 2015 Jul;12(3):620-30

Authors: Costales JL, Kolevzon A

Abstract
Phelan-McDermid syndrome (PMS), also called 22q13.3 deletion syndrome, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, severe speech delays, poor motor tone and function, and autism spectrum disorder (ASD). Although the overall prevalence of PMS is unknown, there have been at least 1200 cases reported worldwide, according to the Phelan-McDermid Syndrome Foundation. PMS is now considered to be a relatively common cause of ASD and intellectual disability, accounting for between 0.5% and 2.0% of cases. The cause of PMS has been isolated to loss of function of one copy of SHANK3, which codes for a master scaffolding protein found in the postsynaptic density of excitatory synapses. Reduced expression of SH3 and multiple ankyrin repeat domains 3 (SHANK3) leads to reduced numbers of dendrites, and impaired synaptic transmission and plasticity. Recent mouse and human neuronal models of PMS have led to important opportunities to develop novel therapeutics, and at least 2 clinical trials are underway, one in the USA, and one in the Netherlands. The SHANK3 pathway may also be relevant to other forms of ASD, and many of the single-gene causes of ASD identified to date appear to converge on several common molecular pathways that underlie synaptic neurotransmission. As a result, treatments developed for PMS may also affect other forms of ASD.

PMID: 25894671 [PubMed - indexed for MEDLINE]

Rett Syndrome: Reaching for Clinical Trials.

March 25, 2016 - 8:38am
Related Articles

Rett Syndrome: Reaching for Clinical Trials.

Neurotherapeutics. 2015 Jul;12(3):631-40

Authors: Pozzo-Miller L, Pati S, Percy AK

Abstract
Rett syndrome (RTT) is a syndromic autism spectrum disorder caused by loss-of-function mutations in MECP2. The methyl CpG binding protein 2 binds methylcytosine and 5-hydroxymethycytosine at CpG sites in promoter regions of target genes, controlling their transcription by recruiting co-repressors and co-activators. Several preclinical studies in mouse models have identified rational molecular targets for drug therapies aimed at correcting the underlying neural dysfunction. These targeted therapies are increasingly translating into human clinical trials. In this review, we present an overview of RTT and describe the current state of preclinical studies in methyl CpG binding protein 2-based mouse models, as well as current clinical trials in individuals with RTT.

PMID: 25861995 [PubMed - indexed for MEDLINE]

The Use of Induced Pluripotent Stem Cell Technology to Advance Autism Research and Treatment.

March 25, 2016 - 8:38am
Related Articles

The Use of Induced Pluripotent Stem Cell Technology to Advance Autism Research and Treatment.

Neurotherapeutics. 2015 Jul;12(3):534-45

Authors: Acab A, Muotri AR

Abstract
Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders sharing a core set of symptoms, including impaired social interaction, language deficits, and repetitive behaviors. While ASDs are highly heritable and demonstrate a clear genetic component, the cellular and molecular mechanisms driving ASD etiology remain undefined. The unavailability of live patient-specific neurons has contributed to the difficulty in studying ASD pathophysiology. The recent advent of induced pluripotent stem cells (iPSCs) has provided the ability to generate patient-specific human neurons from somatic cells. The iPSC field has quickly grown, as researchers have demonstrated the utility of this technology to model several diseases, especially neurologic disorders. Here, we review the current literature around using iPSCs to model ASDs, and discuss the notable findings, and the promise and limitations of this technology. The recent report of a nonsyndromic ASD iPSC model and several previous ASD models demonstrating similar results points to the ability of iPSC to reveal potential novel biomarkers and therapeutics.

PMID: 25851569 [PubMed - indexed for MEDLINE]

Variants of the CNTNAP2 5' promoter as risk factors for autism spectrum disorders: a genetic and functional approach.

March 25, 2016 - 8:38am
Related Articles

Variants of the CNTNAP2 5' promoter as risk factors for autism spectrum disorders: a genetic and functional approach.

Mol Psychiatry. 2015 Jul;20(7):839-49

Authors: Chiocchetti AG, Kopp M, Waltes R, Haslinger D, Duketis E, Jarczok TA, Poustka F, Voran A, Graab U, Meyer J, Klauck SM, Fulda S, Freitag CM

Abstract
Contactin-associated protein-like 2 gene (CNTNAP2), a member of the Neurexin gene superfamily, is one of the best-replicated risk genes for autism spectrum disorders (ASD). ASD are predominately genetically determined neurodevelopmental disorders characterized by impairments of language development, social interaction and communication, as well as stereotyped behavior and interests. Although CNTNAP2 expression levels were proposed to alter ASD risk, no study to date has focused on its 5' promoter. Here, we directly sequenced the CNTNAP2 5' promoter region of 236 German families with one child with ASD and detected four novel variants. Furthermore, we genotyped the three most frequent variants (rs150447075, rs34712024, rs71781329) in an additional sample of 356 families and found nominal association of rs34712024G with ASD and rs71781329GCG[7] with language development. The four novel and the three known minor alleles of the identified variants were predicted to alter transcription factor binding sites (TFBS). At the functional level, the respective sequences spanning these seven variants were bound by nuclear factors. In a luciferase promoter assay, the respective minor alleles showed cell line-specific and differentiation stage-dependent effects at the level of promoter activation. The novel potential rare risk-variant M2, a G>A mutation -215 base pairs 5' of the transcriptional start site, significantly reduced promoter efficiency in HEK293T and in undifferentiated and differentiated neuroblastoid SH-SY5Y cells. This variant was transmitted to a patient with autistic disorder. The under-transmitted, protective minor G allele of the common variant rs34712024, in contrast, increased transcriptional activity. These results lead to the conclusion that the pathomechanism of CNTNAP2 promoter variants on ASD risk is mediated by their effect on TFBSs, and thus confirm the hypothesis that a reduced CNTNAP2 level during neuronal development increases liability for ASD.

PMID: 25224256 [PubMed - indexed for MEDLINE]

Extinction of an instrumental response: a cognitive behavioral assay in Fmr1 knockout mice.

March 25, 2016 - 8:38am
Related Articles

Extinction of an instrumental response: a cognitive behavioral assay in Fmr1 knockout mice.

Genes Brain Behav. 2014 Jun;13(5):451-8

Authors: Sidorov MS, Krueger DD, Taylor M, Gisin E, Osterweil EK, Bear MF

Abstract
Fragile X (FX) is the most common genetic cause of intellectual disability and autism. Previous studies have shown that partial inhibition of metabotropic glutamate receptor signaling is sufficient to correct behavioral phenotypes in a mouse model of FX, including audiogenic seizures, open-field hyperactivity and social behavior. These phenotypes model well the epilepsy (15%), hyperactivity (20%) and autism (30%) that are comorbid with FX in human patients. Identifying reliable and robust mouse phenotypes to model cognitive impairments is critical considering the 90% comorbidity of FX and intellectual disability. Recent work characterized a five-choice visuospatial discrimination assay testing cognitive flexibility, in which FX model mice show impairments associated with decreases in synaptic proteins in prefrontal cortex (PFC). In this study, we sought to determine whether instrumental extinction, another process requiring PFC, is altered in FX model mice, and whether downregulation of metabotropic glutamate receptor signaling pathways is sufficient to correct both visuospatial discrimination and extinction phenotypes. We report that instrumental extinction is consistently exaggerated in FX model mice. However, neither the extinction phenotype nor the visuospatial discrimination phenotype is corrected by approaches targeting metabotropic glutamate receptor signaling. This work describes a novel behavioral extinction assay to model impaired cognition in mouse models of neurodevelopmental disorders, provides evidence that extinction is exaggerated in the FX mouse model and suggests possible limitations of metabotropic glutamate receptor-based pharmacotherapy.

PMID: 24684608 [PubMed - indexed for MEDLINE]

Social cognition and underlying cognitive mechanisms in children with an extra X chromosome: a comparison with autism spectrum disorder.

March 25, 2016 - 8:38am
Related Articles

Social cognition and underlying cognitive mechanisms in children with an extra X chromosome: a comparison with autism spectrum disorder.

Genes Brain Behav. 2014 Jun;13(5):459-67

Authors: van Rijn S, Stockmann L, van Buggenhout G, van Ravenswaaij-Arts C, Swaab H

Abstract
Individuals with an extra X chromosome are at increased risk for autism symptoms. This study is the first to assess theory of mind and facial affect labeling in children with an extra X chromosome. Forty-six children with an extra X chromosome (29 boys with Klinefelter syndrome and 17 girls with Trisomy X), 56 children with autism spectrum disorder (ASD) and 88 non-clinical controls, aged 9-18 years, were included. Similar to children with ASD, children with an extra X chromosome showed significant impairments in social cognition. Regression analyses showed that different cognitive functions predicted social cognitive skills in the extra X and ASD groups. The social cognitive deficits were similar for boys and girls with an extra X chromosome, and not specific for a subgroup with high Autism Diagnostic Interview Revised autism scores. Thus, children with an extra X chromosome show social cognitive deficits, which may contribute to social dysfunction, not only in children showing a developmental pattern that is 'typical' for autism but also in those showing mild or late presenting autism symptoms. Our findings may also help explain variance in type of social deficit: children may show similar social difficulties, but these may arise as a consequence of different underlying information processing deficits.

PMID: 24655419 [PubMed - indexed for MEDLINE]

Pages