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Patterns and predictors of anxiety among siblings of children with autism spectrum disorders.

January 29, 2014 - 7:49am
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Patterns and predictors of anxiety among siblings of children with autism spectrum disorders.

J Autism Dev Disord. 2013 Jun;43(6):1336-46

Authors: Shivers CM, Deisenroth LK, Taylor JL

Abstract
The purpose of this study was to examine patterns of anxiety among siblings of children with autism spectrum disorders (ASD), and determine the characteristics of the child with ASD and their parents that predicted anxiety. Data was collected from 1,755 siblings of children with ASD whose families participated in the Simons Simplex Collection; siblings ranged in age from 3 to 18 years (M = 9 years). Male siblings were at increased risk for sub-clinical anxiety problems during middle childhood. Parental history of anxiety disorders, higher maternal pragmatic language, and more proband behavior problems predicted higher anxiety. While siblings overall did not show elevated anxiety symptoms, higher rates of sub-clinical anxiety problems among males and siblings in middle childhood are cause for concern.

PMID: 23076507 [PubMed - indexed for MEDLINE]

Brief report: altered social behavior in isolation-reared Fmr1 knockout mice.

January 29, 2014 - 7:49am
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Brief report: altered social behavior in isolation-reared Fmr1 knockout mice.

J Autism Dev Disord. 2013 Jun;43(6):1452-8

Authors: Heitzer AM, Roth AK, Nawrocki L, Wrenn CC, Valdovinos MG

Abstract
Social behavior abnormalities in Fragile X syndrome (FXS) are characterized by social withdrawal, anxiety, and deficits in social cognition. To assess these deficits, a model of FXS, the Fmr1 knockout mouse (Fmr1 KO), has been utilized. This mouse model has a null mutation in the fragile X mental retardation 1 gene (Fmr1) and displays physical and behavioral characteristics similar to humans with FXS. Several studies have investigated the social behavior of this model, but the results on the behavioral phenotype have not been consistent. In order to further characterize the social behavior in the knockout, isolation-reared Fmr1 KO were evaluated to determine if they differ in their social behavior compared to wild-type littermate controls. Differences by genotype were not observed in social approach behavior; however, the knockout mice showed a significantly reduced preference for social novelty and decreased sniff time in the sociability phase. These findings add to the growing body of knowledge on the subtle differences in social behavior shown by the Fmr1 knockout mice, and that differences occur when the subjects are isolation-reared. Validity of the model and possible changes to methodology are discussed.

PMID: 23015112 [PubMed - indexed for MEDLINE]

Strong genetic influences on measures of behavioral-regulation among inbred rat strains.

January 28, 2014 - 6:46am
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Strong genetic influences on measures of behavioral-regulation among inbred rat strains.

Genes Brain Behav. 2013 Jul;12(5):490-502

Authors: Richards JB, Lloyd DR, Kuehlewind B, Militello L, Paredez M, Solberg Woods L, Palmer AA

Abstract
A fundamental challenge for any complex nervous system is to regulate behavior in response to environmental challenges. Three measures of behavioral-regulation were tested in a panel of eight inbred rat strains. These measures were: (1) sensation seeking as assessed by locomotor response to novelty and the sensory reinforcing effects of light onset, (2) attention and impulsivity, as measured by a choice reaction time task and (3) impulsivity as measured by a delay discounting task. Deficient behavioral-regulation has been linked to a number of psychopathologies, including ADHD, Schizophrenia, Autism, drug abuse and eating disorders. Eight inbred rat strains (August Copenhagen Irish, Brown Norway, Buffalo, Fischer 344, Wistar Kyoto, Spontaneous Hypertensive Rat, Lewis, Dahl Salt Sensitive) were tested. With n = 9 for each strain, we observed robust strain differences for all tasks; heritability was estimated between 0.43 and 0.66. Performance of the eight inbred rat strains on the choice reaction time task was compared to the performance of outbred Sprague Dawley (n = 28) and Heterogeneous strain rats (n = 48). The results indicate a strong genetic influence on complex tasks related to behavioral-regulation and indicate that some of the measures tap common genetically driven processes. Furthermore, our results establish the potential for future studies aimed at identifying specific alleles that influence variability for these traits. Identification of such alleles could contribute to our understanding of the molecular genetic basis of behavioral-regulation, which is of fundamental importance and likely contributes to multiple psychiatric disorders.

PMID: 23710681 [PubMed - indexed for MEDLINE]

Autism spectrum disorder, flea and tick medication, and adjustments for exposure misclassification: the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study.

January 25, 2014 - 8:57am

Autism spectrum disorder, flea and tick medication, and adjustments for exposure misclassification: the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study.

Environ Health. 2014 Jan 23;13(1):3

Authors: Keil AP, Daniels JL, Hertz-Picciotto I

Abstract
BACKGROUND: The environmental contribution to autism spectrum disorders (ASD) is largely unknown, but household pesticides are receiving increased attention. We examined associations between ASD and maternally-reported use of imidacloprid, a common flea and tick treatment for pets.
METHODS: Bayesian logistic models were used to estimate the association between ASD and imidacloprid and to correct for potential differential exposure misclassification due to recall in a case control study of ASD.
RESULTS: Our analytic dataset included complete information for 262 typically developing controls and 407 children with ASD. Compared with exposure among controls, the odds of prenatal imidacloprid exposure among children with ASD were slightly higher, with an odds ratio (OR) of 1.3 (95% Credible Interval [CrI] 0.78, 2.2). A susceptibility window analysis yielded higher ORs for exposures during pregnancy than for early life exposures, whereas limiting to frequent users of imidacloprid, the OR increased to 2.0 (95% CI 1.0, 3.9).
CONCLUSIONS: Within plausible estimates of sensitivity and specificity, the association could result from exposure misclassification alone. The association between imidacloprid exposure and ASD warrants further investigation, and this work highlights the need for validation studies regarding prenatal exposures in ASD.

PMID: 24456651 [PubMed - as supplied by publisher]

Identifying phenotypic signatures of neuropsychiatric disorders from electronic medical records.

January 25, 2014 - 8:57am
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Identifying phenotypic signatures of neuropsychiatric disorders from electronic medical records.

J Am Med Inform Assoc. 2013 Dec;20(e2):e297-305

Authors: Lyalina S, Percha B, LePendu P, Iyer SV, Altman RB, Shah NH

Abstract
OBJECTIVE: Mental illness is the leading cause of disability in the USA, but boundaries between different mental illnesses are notoriously difficult to define. Electronic medical records (EMRs) have recently emerged as a powerful new source of information for defining the phenotypic signatures of specific diseases. We investigated how EMR-based text mining and statistical analysis could elucidate the phenotypic boundaries of three important neuropsychiatric illnesses-autism, bipolar disorder, and schizophrenia.
METHODS: We analyzed the medical records of over 7000 patients at two facilities using an automated text-processing pipeline to annotate the clinical notes with Unified Medical Language System codes and then searching for enriched codes, and associations among codes, that were representative of the three disorders. We used dimensionality-reduction techniques on individual patient records to understand individual-level phenotypic variation within each disorder, as well as the degree of overlap among disorders.
RESULTS: We demonstrate that automated EMR mining can be used to extract relevant drugs and phenotypes associated with neuropsychiatric disorders and characteristic patterns of associations among them. Patient-level analyses suggest a clear separation between autism and the other disorders, while revealing significant overlap between schizophrenia and bipolar disorder. They also enable localization of individual patients within the phenotypic 'landscape' of each disorder.
CONCLUSIONS: Because EMRs reflect the realities of patient care rather than idealized conceptualizations of disease states, we argue that automated EMR mining can help define the boundaries between different mental illnesses, facilitate cohort building for clinical and genomic studies, and reveal how clear expert-defined disease boundaries are in practice.

PMID: 23956017 [PubMed - indexed for MEDLINE]

Genetic Variants of Neurotransmitter-Related Genes and miRNAs in Egyptian Autistic Patients.

January 24, 2014 - 8:37am

Genetic Variants of Neurotransmitter-Related Genes and miRNAs in Egyptian Autistic Patients.

ScientificWorldJournal. 2013 Dec 23;2013:670621

Authors: Salem AM, Ismail S, Zarouk WA, Abdul Baky O, Sayed AA, Abd El-Hamid S, Salem S

Abstract
Autism is a neurodevelopmental disorder with indisputable evidence for a genetic component. This work studied the association of autism with genetic variations in neurotransmitter-related genes, including MAOA uVNTR, MAOB rs1799836, and DRD2 TaqI A in 53 autistic patients and 30 healthy individuals. The study also analyzed sequence variations of miR-431 and miR-21. MAOA uVNTR was genotyped by PCR, MAOB and DRD2 polymorphisms were analyzed by PCR-based RFLP, and miR-431 and miR-21 were sequenced. Low expressing allele of MAOA uVNTR was frequently higher in female patients compared to that in controls (OR = 2.25). MAOB G allele frequency was more significantly increased in autistic patients than in controls (P < 0.001 for both males and females). DRD2 A1+ genotype increased autism risk (OR = 5.1). Severity of autism tends to be slightly affected by MAOA/B genotype. Plasma MAOB activity was significantly reduced in G than in A allele carrying males. There was no significant difference in patients and maternal plasma MAOA/B activity compared to controls. Neither mutations nor SNPs in miR-431 and miR-21 were found among studied patients. This study threw light on some neurotransmitter-related genes suggesting their potential role in Autism pathogenesis that warrants further studies and much consideration.

PMID: 24453887 [PubMed - in process]

Cell type-specific expression analysis to identify putative cellular mechanisms for neurogenetic disorders.

January 24, 2014 - 8:37am

Cell type-specific expression analysis to identify putative cellular mechanisms for neurogenetic disorders.

J Neurosci. 2014 Jan 22;34(4):1420-31

Authors: Xu X, Wells AB, O'Brien DR, Nehorai A, Dougherty JD

Abstract
Recent advances have substantially increased the number of genes that are statistically associated with complex genetic disorders of the CNS such as autism and schizophrenia. It is now clear that there will likely be hundreds of distinct loci contributing to these disorders, underscoring a remarkable genetic heterogeneity. It is unclear whether this genetic heterogeneity indicates an equal heterogeneity of cellular mechanisms for these diseases. The commonality of symptoms across patients suggests there could be a functional convergence downstream of these loci upon a limited number of cell types or circuits that mediate the affected behaviors. One possible mechanism for this convergence would be the selective expression of at least a subset of these genes in the cell types that comprise these circuits. Using profiling data from mice and humans, we have developed and validated an approach, cell type-specific expression analysis, for identifying candidate cell populations likely to be disrupted across sets of patients with distinct genetic lesions. Using human genetics data and postmortem gene expression data, our approach can correctly identify the cell types for disorders of known cellular etiology, including narcolepsy and retinopathies. Applying this approach to autism, a disease where the cellular mechanism is unclear, indicates there may be multiple cellular routes to this disorder. Our approach may be useful for identifying common cellular mechanisms arising from distinct genetic lesions.

PMID: 24453331 [PubMed - in process]

Reelin gene variants and risk of autism spectrum disorders: An integrated meta-analysis.

January 24, 2014 - 8:37am

Reelin gene variants and risk of autism spectrum disorders: An integrated meta-analysis.

Am J Med Genet B Neuropsychiatr Genet. 2014 Jan 22;

Authors: Wang Z, Hong Y, Zou L, Zhong R, Zhu B, Shen N, Chen W, Lou J, Ke J, Zhang T, Wang W, Miao X

Abstract
Autism spectrum disorder (ASD) is a severe neurological disorder with a high degree of heritability. Reelin gene (RELN), which plays a crucial role in the migration and positioning of neurons during brain development, has been strongly posed as a candidate gene for ASD. Genetic variants in RELN have been investigated as risk factors of ASD in numerous epidemiologic studies but with inconclusive results. To clearly discern the effects of RELN variants on ASD, the authors conducted a meta-analysis integrating case-control and transmission disequilibrium test (TDT) studies published through 2001 to 2013. Odds ratios (ORs) with 95% confidence intervals were used to estimate the associations between three RELN variants (rs736707, rs362691, and GGC repeat variant) and ASD. In overall meta-analysis, the summary ORs for rs736707, rs362691, and GGC repeat variant were 1.11 [95% confidence interval (CI): 0.80-1.54], 0.69 (95% CI: 0.56-0.86), and 1.09 (95% CI: 0.97-1.23), respectively. Besides, positive result was also obtained in subgroup of broadly-defined ASD for rs362691 (OR = 0.67, 95% CI: 0.52-0.86). Our meta-analysis revealed that the RELN rs362691, rather than rs736707 or GGC repeat variant, might contribute significantly to ASD risk. © 2014 Wiley Periodicals, Inc.

PMID: 24453138 [PubMed - as supplied by publisher]

[Subchromosomal microdeletion identified by molecular karyotyping using DNA microarrays (array CGH) in Rett syndrome girls negative for MECP2 gene mutations].

January 24, 2014 - 8:37am
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[Subchromosomal microdeletion identified by molecular karyotyping using DNA microarrays (array CGH) in Rett syndrome girls negative for MECP2 gene mutations].

Zh Nevrol Psikhiatr Im S S Korsakova. 2013;113(10):63-8

Authors: Vorsanova SG, Iurov IIu, Voinova VIu, Kurinnaia OS, Zelenova MA, Demidova IA, Ulas EV, Iurov IuB

Abstract
Molecular karyotyping using DNA microarrays (array CGH) was applied for identification of subchromosomal microdeletions in a cohort of 12 girls with clinical features of RETT syndrome, but negative for MECP2 gene mutations. Recurrent microdeletions of MECP2 gene in chromosome X (locus Xq28) were identified in 5 girls of 12 studied. Probably RTT girls with subchromosomic microdeletions in Xq28 could represent a special subtype of the disease, which appears as clinically milder than the classic form of disease. In one case, an atypical form of RTT was associated with genomic abnormalities affecting CDKL5 gene and region critical for microdeletion Prader-Willi and Angelman syndromes (15q11.2). In addition, data are presented for the first time that genetic variation in regions 3p13, 3q27.1, and 1q21.1-1q21.2 could associate with RTT-like clinical manifestations. Without application of molecular karyotyping technology and bioinformatic method of assessing the pathogenic significance of genomic rearrangements these RTT-like girls negative for MECP2 gene mutations were considered as cases of idiopathic mental retardation associated with autism. It should be noted that absence of intragenic mutations in MECP2 gene is not sufficient criteria to reject the clinical diagnosis of RTT. To avoid errors in the genetic diagnosis of this genetically heterogeneous brain disease molecular cytogenetic studies using high resolution oligonucleotide array CGH (molecular karyotyping) are needed.

PMID: 24300809 [PubMed - indexed for MEDLINE]

Cloning and characterization of the promoter regions from the parent and paralogous creatine transporter genes.

January 24, 2014 - 8:37am
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Cloning and characterization of the promoter regions from the parent and paralogous creatine transporter genes.

Gene. 2014 Jan 10;533(2):488-93

Authors: Ndika JD, Lusink V, Beaubrun C, Kanhai W, Martinez-Munoz C, Jakobs C, Salomons GS

Abstract
Interconversion between phosphocreatine and creatine, catalyzed by creatine kinase is crucial in the supply of ATP to tissues with high energy demand. Creatine's importance has been established by its use as an ergogenic aid in sport, as well as the development of intellectual disability in patients with congenital creatine deficiency. Creatine biosynthesis is complemented by dietary creatine uptake. Intracellular transport of creatine is carried out by a creatine transporter protein (CT1/CRT/CRTR) encoded by the SLC6A8 gene. Most tissues express this gene, with highest levels detected in skeletal muscle and kidney. There are lower levels of the gene detected in colon, brain, heart, testis and prostate. The mechanism(s) by which this regulation occurs is still poorly understood. A duplicated unprocessed pseudogene of SLC6A8-SLC6A10P has been mapped to chromosome 16p11.2 (contains the entire SLC6A8 gene, plus 2293 bp of 5'flanking sequence and its entire 3'UTR). Expression of SLC6A10P has so far only been shown in human testis and brain. It is still unclear as to what is the function of SLC6A10P. In a patient with autism, a chromosomal breakpoint that intersects the 5'flanking region of SLC6A10P was identified; suggesting that SLC6A10P is a non-coding RNA involved in autism. Our aim was to investigate the presence of cis-acting factor(s) that regulate expression of the creatine transporter, as well as to determine if these factors are functionally conserved upstream of the creatine transporter pseudogene. Via gene-specific PCR, cloning and functional luciferase assays we identified a 1104 bp sequence proximal to the mRNA start site of the SLC6A8 gene with promoter activity in five cell types. The corresponding 5'flanking sequence (1050 bp) on the pseudogene also had promoter activity in all 5 cell lines. Surprisingly the pseudogene promoter was stronger than that of its parent gene in 4 of the cell lines tested. To the best of our knowledge, this is the first experimental evidence of a pseudogene with stronger promoter activity than its parental gene.

PMID: 24144841 [PubMed - indexed for MEDLINE]

Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology.

January 24, 2014 - 8:37am
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Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology.

Nat Med. 2013 Nov;19(11):1473-7

Authors: Udagawa T, Farny NG, Jakovcevski M, Kaphzan H, Alarcon JM, Anilkumar S, Ivshina M, Hurt JA, Nagaoka K, Nalavadi VC, Lorenz LJ, Bassell GJ, Akbarian S, Chattarji S, Klann E, Richter JD

Abstract
Fragile X syndrome (FXS), the most common cause of inherited mental retardation and autism, is caused by transcriptional silencing of FMR1, which encodes the translational repressor fragile X mental retardation protein (FMRP). FMRP and cytoplasmic polyadenylation element-binding protein (CPEB), an activator of translation, are present in neuronal dendrites, are predicted to bind many of the same mRNAs and may mediate a translational homeostasis that, when imbalanced, results in FXS. Consistent with this possibility, Fmr1(-/y); Cpeb1(-/-) double-knockout mice displayed amelioration of biochemical, morphological, electrophysiological and behavioral phenotypes associated with FXS. Acute depletion of CPEB1 in the hippocampus of adult Fmr1(-/y) mice rescued working memory deficits, demonstrating reversal of this FXS phenotype. Finally, we find that FMRP and CPEB1 balance translation at the level of polypeptide elongation. Our results suggest that disruption of translational homeostasis is causal for FXS and that the maintenance of this homeostasis by FMRP and CPEB1 is necessary for normal neurologic function.

PMID: 24141422 [PubMed - indexed for MEDLINE]

The effect of the Taq1A variant in the dopamine D₂ receptor gene and common CYP2D6 alleles on prolactin levels in risperidone-treated boys.

January 24, 2014 - 8:37am
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The effect of the Taq1A variant in the dopamine D₂ receptor gene and common CYP2D6 alleles on prolactin levels in risperidone-treated boys.

Pharmacogenet Genomics. 2013 Sep;23(9):487-93

Authors: Roke Y, van Harten PN, Franke B, Galesloot TE, Boot AM, Buitelaar JK

Abstract
OBJECTIVE: To investigate the effect of the Taq1A variant in the Dopamine D2 receptor gene (DRD2) and common functional genetic variants in the cytochrome P450 2D6 gene (CYP2D6) on prolactin levels in risperidone-treated boys with autism spectrum disorders and disruptive behavior disorders.
METHODS: Forty-seven physically healthy 10-year-old to 19-year-old boys with autism spectrum disorders and/or disruptive behavior disorders, chronically treated (mean 52 months, range 16-126 months) with an antipsychotic, were recruited into this observational study. Prolactin levels, hyperprolactinemia, risperidone levels, and 9-hydroxyrisperidone levels were assessed and the participants were genotyped for common CYP2D6 polymorphisms and the Taq1A allele of the dopamine D2 receptor gene. Group differences were tested using Student's t-test, χ², and logistic regression analysis.
RESULTS: Prolactin levels were associated positively and significantly with risperidone levels (P=0.05), 9-hydroxyrisperidone levels (P≤0.0001), and with the oral risperidone dose in milligrams per kilogram (P≤0.0001). Furthermore, multiple regression analysis showed no correlations between prolactin level and the presence of at least one Taq1A A1 allele of the DRD2 gene (P=0.12).
CONCLUSION: Although CYP2D6 might have an effect, the presence of at least one Taq1A A1 allele of the D2DR gene did not contribute toward susceptibility to risperidone-induced hyperprolactinemia, and as a result, toward prolactin-related adverse events such as amenorrhea, galactorrhea, and sexual dysfunctioning.

PMID: 23851570 [PubMed - indexed for MEDLINE]

Fragile X syndrome due to a missense mutation.

January 23, 2014 - 10:54am

Fragile X syndrome due to a missense mutation.

Eur J Hum Genet. 2014 Jan 22;

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.European Journal of Human Genetics advance online publication, 22 January 2014; doi:10.1038/ejhg.2013.311.

PMID: 24448548 [PubMed - as supplied by publisher]

Altered social behaviours in neurexin 1α knockout mice resemble core symptoms in neurodevelopmental disorders.

January 22, 2014 - 7:41am
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Altered social behaviours in neurexin 1α knockout mice resemble core symptoms in neurodevelopmental disorders.

PLoS One. 2013;8(6):e67114

Authors: Grayton HM, Missler M, Collier DA, Fernandes C

Abstract
BACKGROUND: Copy number variants have emerged as an important genomic cause of common, complex neurodevelopmental disorders. These usually change copy number of multiple genes, but deletions at 2p16.3, which have been associated with autism, schizophrenia and mental retardation, affect only the neurexin 1 gene, usually the alpha isoform. Previous analyses of neurexin 1α (Nrxn1α) knockout (KO) mouse as a model of these disorders have revealed impairments in synaptic transmission but failed to reveal defects in social behaviour, one of the core symptoms of autism.
METHODS: We performed a detailed investigation of the behavioural effects of Nrxn1α deletion in mice bred onto a pure genetic background (C57BL/6J) to gain a better understanding of its role in neurodevelopmental disorders. Wildtype, heterozygote and homozygote Nrxn1α KO male and female mice were tested in a battery of behavioural tests (n = 9-16 per genotype, per sex).
RESULTS: In homozygous Nrxn1α KO mice, we observed altered social approach, reduced social investigation, and reduced locomotor activity in novel environments. In addition, male Nrxn1α KO mice demonstrated an increase in aggressive behaviours.
CONCLUSIONS: These are the first experimental data that associate a deletion of Nrxn1α with alterations of social behaviour in mice. Since this represents one of the core symptom domains affected in autism spectrum disorders and schizophrenia in humans, our findings suggest that deletions within NRXN1 found in patients may be responsible for the impairments seen in social behaviours, and that the Nrxn1α KO mice are a useful model of human neurodevelopmental disorder.

PMID: 23840597 [PubMed - indexed for MEDLINE]

IL1RAPL1 associated with mental retardation and autism regulates the formation and stabilization of glutamatergic synapses of cortical neurons through RhoA signaling pathway.

January 22, 2014 - 7:41am
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IL1RAPL1 associated with mental retardation and autism regulates the formation and stabilization of glutamatergic synapses of cortical neurons through RhoA signaling pathway.

PLoS One. 2013;8(6):e66254

Authors: Hayashi T, Yoshida T, Ra M, Taguchi R, Mishina M

Abstract
Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) is associated with X-linked mental retardation and autism spectrum disorder. We found that IL1RAPL1 regulates synapse formation of cortical neurons. To investigate how IL1RAPL1 controls synapse formation, we here screened IL1RAPL1-interacting proteins by affinity chromatography and mass spectroscopy. IL1RAPL1 interacted with Mcf2-like (Mcf2l), a Rho guanine nucleotide exchange factor, through the cytoplasmic Toll/IL-1 receptor domain. Knockdown of endogenous Mcf2l and treatment with an inhibitor of Rho-associated protein kinase (ROCK), the downstream kinase of RhoA, suppressed IL1RAPL1-induced excitatory synapse formation of cortical neurons. Furthermore, we found that the expression of IL1RAPL1 affected the turnover of AMPA receptor subunits. Insertion of GluA1-containing AMPA receptors to the cell surface was decreased, whereas that of AMPA receptors composed of GluA2/3 was enhanced. Mcf2l knockdown and ROCK inhibitor treatment diminished the IL1RAPL1-induced changes of AMPA receptor subunit insertions. Our results suggest that Mcf2l-RhoA-ROCK signaling pathway mediates IL1RAPL1-dependent formation and stabilization of glutamatergic synapses of cortical neurons.

PMID: 23785489 [PubMed - indexed for MEDLINE]

Widespread differences in cortex DNA methylation of the "language gene" CNTNAP2 between humans and chimpanzees.

January 18, 2014 - 6:51am

Widespread differences in cortex DNA methylation of the "language gene" CNTNAP2 between humans and chimpanzees.

Epigenetics. 2014 Jan 16;9(4)

Authors: Schneider E, El Hajj N, Richter S, Roche-Santiago J, Nanda I, Schempp W, Riederer P, Navarro B, Bontrop RE, Kondova I, Scholz CJ, Haaf T

Abstract
CNTNAP2, one of the largest genes in the human genome, has been linked to human-specific language abilities and neurodevelopmental disorders. Our hypothesis is that epigenetic rather than genetic changes have accelerated the evolution of the human brain. To compare the cortex DNA methylation patterns of human and chimpanzee CNTNAP2 at ultra-high resolution, we combined methylated DNA immunoprecipitation (MeDIP) with NimbleGen tiling arrays for the orthologous gene and flanking sequences. Approximately 1.59 Mb of the 2.51 Mb target region could be aligned and analyzed with a customized algorithm in both species. More than one fifth (0.34 Mb) of the analyzed sequence throughout the entire gene displayed significant methylation differences between six human and five chimpanzee cortices. One of the most striking interspecies differences with 28% methylation in human and 59% in chimpanzee cortex (by bisulfite pyrosequencing) lies in a region 300 bp upstream of human SNP rs7794745 which has been associated with autism and parent-of-origin effects. Quantitative real-time RT PCR revealed that the protein-coding splice variant CNTNAP2-201 is 1.6-fold upregulated in human cortex, compared with the chimpanzee. Transcripts CNTNAP2-001, -002, and -003 did not show skewed allelic expression, which argues against CNTNAP2 imprinting, at least in adult human brain. Collectively, our results suggest widespread cortex DNA methylation changes in CNTNAP2 since the human-chimpanzee split, supporting a role for CNTNAP2 fine-regulation in human-specific language and communication traits.

PMID: 24434791 [PubMed - as supplied by publisher]

The role of de novo mutations in the genetics of autism spectrum disorders.

January 17, 2014 - 8:45am

The role of de novo mutations in the genetics of autism spectrum disorders.

Nat Rev Genet. 2014 Jan 16;

Authors: Ronemus M, Iossifov I, Levy D, Wigler M

Abstract
The identification of the genetic components of autism spectrum disorders (ASDs) has advanced rapidly in recent years, particularly with the demonstration of de novo mutations as an important source of causality. We review these developments in light of genetic models for ASDs. We consider the number of genetic loci that underlie ASDs and the relative contributions from different mutational classes, and we discuss possible mechanisms by which these mutations might lead to dysfunction. We update the two-class risk genetic model for autism, especially in regard to children with high intelligence quotients.

PMID: 24430941 [PubMed - as supplied by publisher]

Necrosis is increased in lymphoblastoid cell lines from children with autism compared with their non-autistic siblings under conditions of oxidative and nitrosative stress.

January 17, 2014 - 8:45am
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Necrosis is increased in lymphoblastoid cell lines from children with autism compared with their non-autistic siblings under conditions of oxidative and nitrosative stress.

Mutagenesis. 2013 Jul;28(4):475-84

Authors: Main PA, Thomas P, Esterman A, Fenech MF

Abstract
Autism spectrum disorders are a heterogeneous group of neurodevelopmental conditions characterised by impairments in reciprocal social interaction, communication and stereotyped behaviours. As increased DNA damage events have been observed in a range of other neurological disorders, it was hypothesised that they would be elevated in lymphoblastoid cell lines (LCLs) obtained from children with autism compared with their non-autistic siblings. Six case-sibling pairs of LCLs from children with autistic disorder and their non-autistic siblings were obtained from the Autism Genetic Resource Exchange (AGRE) and cultured in standard RPMI-1640 tissue culture medium. Cells were exposed to medium containing either 0, 25, 50, 100 and 200 µM hydrogen peroxide (an oxidative stressor) or 0, 5, 10, 20 and 40 µM s-nitroprusside (a nitric oxide producer) for 1h. Following exposure, the cells were microscopically scored for DNA damage, cytostasis and cytotoxicity biomarkers as measured using the cytokinesis-block micronucleus cytome assay. Necrosis was significantly increased in cases relative to controls when exposed to oxidative and nitrosative stress (P = 0.001 and 0.01, respectively). Nuclear division index was significantly lower in LCLs from children with autistic disorder than their non-autistic siblings when exposed to hydrogen peroxide (P = 0.016), but there was no difference in apoptosis, micronucleus frequency, nucleoplasmic bridges or nuclear buds. Exposure to s-nitroprusside significantly increased the number of micronuclei in non-autistic siblings compared with cases (P = 0.003); however, other DNA damage biomarkers, apoptosis and nuclear division did not differ significantly between groups. The findings of this study show (i) that LCLs from children with autism are more sensitive to necrosis under conditions of oxidative and nitrosative stress than their non-autistic siblings and (ii) refutes the hypothesis that children with autistic disorder are abnormally susceptible to DNA damage.

PMID: 23766106 [PubMed - indexed for MEDLINE]

Association between OXTR and clinical phenotypes of autism spectrum disorders.

January 17, 2014 - 8:45am
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Association between OXTR and clinical phenotypes of autism spectrum disorders.

Psychiatry Res. 2013 Jun 30;208(1):99-100

Authors: Egawa J, Watanabe Y, Endo T, Tamura R, Masuzawa N, Someya T

PMID: 23219106 [PubMed - indexed for MEDLINE]

Exploring inhibitory deficits in female premutation carriers of fragile X syndrome: Through eye movements.

January 16, 2014 - 7:25am

Exploring inhibitory deficits in female premutation carriers of fragile X syndrome: Through eye movements.

Brain Cogn. 2014 Jan 11;85C:201-208

Authors: Shelton AL, Cornish K, Kraan C, Georgiou-Karistianis N, Metcalfe SA, Bradshaw JL, Hocking DR, Archibald AD, Cohen J, Trollor JN, Fielding J

Abstract
There is evidence which demonstrates that a subset of males with a premutation CGG repeat expansion (between 55 and 200 repeats) of the fragile X mental retardation 1 gene exhibit subtle deficits of executive function that progressively deteriorate with increasing age and CGG repeat length. However, it remains unclear whether similar deficits, which may indicate the onset of more severe degeneration, are evident in female PM-carriers. In the present study we explore whether female PM-carriers exhibit deficits of executive function which parallel those of male PM-carriers. Fourteen female fragile X premutation carriers without fragile X-associated tremor/ataxia syndrome and fourteen age, sex, and IQ matched controls underwent ocular motor and neuropsychological tests of select executive processes, specifically of response inhibition and working memory. Group comparisons revealed poorer inhibitory control for female premutation carriers on ocular motor tasks, in addition to demonstrating some difficulties in behaviour self-regulation, when compared to controls. A negative correlation between CGG repeat length and antisaccade error rates for premutation carriers was also found. Our preliminary findings indicate that impaired inhibitory control may represent a phenotype characteristic which may be a sensitive risk biomarker within this female fragile X premutation population.

PMID: 24424424 [PubMed - as supplied by publisher]

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