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Serotonin transporter genotype impacts amygdala habituation in youth with autism spectrum disorders.

January 17, 2015 - 6:51am
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Serotonin transporter genotype impacts amygdala habituation in youth with autism spectrum disorders.

Soc Cogn Affect Neurosci. 2014 Jun;9(6):832-8

Authors: Wiggins JL, Swartz JR, Martin DM, Lord C, Monk CS

Abstract
Failure of the amygdala to habituate, or decrease response intensity, to repeatedly presented faces may be one mechanism by which individuals with autism spectrum disorders (ASD) develop and maintain social symptoms. However, genetic influences on habituation in ASD have not been examined. We hypothesized that serotonin transporter-linked promoter region (5-HTTLPR) genotype affects change in amygdala response to repeated sad faces differently in individuals with ASD vs healthy controls. Forty-four youth with ASD and 65 controls aged 8-19 years were genotyped and underwent an event-related functional magnetic resonance imaging scan where they identified the gender of emotional faces presented for 250 ms. The first half of the run was compared with the second half to assess habituation. 5-HTTLPR genotype influences amygdala habituation to sad faces differently for individuals with ASD vs controls. The genotype-by-diagnosis-by-run half interaction was driven by individuals with ASD and low expressing genotypes (S/S, S/L(G) and L(G)/L(G)), who trended toward sensitization (increase in amygdala activation) and whose habituation scores significantly differed from individuals with ASD and higher expressing genotypes (L(A)/L(A), S/L(A) and L(A)/L(G)) as well as controls with low expressing genotypes. Our results show that amygdala response to social stimuli in ASD, which may contribute to social symptoms, is genetically influenced.

PMID: 23526151 [PubMed - indexed for MEDLINE]

HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism.

January 16, 2015 - 6:16am
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HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism.

Cell Rep. 2014 Mar 27;6(6):1139-52

Authors: Weyn-Vanhentenryck SM, Mele A, Yan Q, Sun S, Farny N, Zhang Z, Xue C, Herre M, Silver PA, Zhang MQ, Krainer AR, Darnell RB, Zhang C

Abstract
The RNA binding proteins Rbfox1/2/3 regulate alternative splicing in the nervous system, and disruption of Rbfox1 has been implicated in autism. However, comprehensive identification of functional Rbfox targets has been challenging. Here, we perform HITS-CLIP for all three Rbfox family members in order to globally map, at a single-nucleotide resolution, their in vivo RNA interaction sites in the mouse brain. We find that the two guanines in the Rbfox binding motif UGCAUG are critical for protein-RNA interactions and crosslinking. Using integrative modeling, these interaction sites, combined with additional datasets, define 1,059 direct Rbfox target alternative splicing events. Over half of the quantifiable targets show dynamic changes during brain development. Of particular interest are 111 events from 48 candidate autism-susceptibility genes, including syndromic autism genes Shank3, Cacna1c, and Tsc2. Alteration of Rbfox targets in some autistic brains is correlated with downregulation of all three Rbfox proteins, supporting the potential clinical relevance of the splicing-regulatory network.

PMID: 24613350 [PubMed - indexed for MEDLINE]

ADHD bör uppmärksammas mer - tidiga insatser spar lidande.

January 15, 2015 - 8:46am
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ADHD bör uppmärksammas mer - tidiga insatser spar lidande.

Lakartidningen. 2014;111

Authors: Fernell E, Nylander L, Kadesjö B, Gillberg C

Abstract
ADHD is a common neurodevelopmental/neuropsychiatric disorder affecting about 5 percent of children. About 2-3 percent meet diagnostic criteria in adulthood as well. The core symptoms include inattention with or without hyperactivity/restlessness and impulsivity. The main cognitive deficit involves executive functions, probably related to a weak reward system. Symptoms will affect daily functioning at home, among friends and at school/work. In girls and women particularly, a correct diagnosis of ADHD is often late, or is not at all appropriately considered. Co-existing disorders are common; dyslexia, developmental coordination disorder, emotional lability, conduct disorder, autistic symptoms, obsessive compulsive disorder, depression, bipolar disorder, Tourette syndrome, eating disorder, sleeping disorder, and substance abuse. Extensive research in ADHD has increased knowledge in genetics, neurobiology, neuropsychology, intervention, and treatment. Despite this, many individuals with ADHD are not offered a correct assessment, and accordingly, not given appropriate support and treatment.

PMID: 25584596 [PubMed - as supplied by publisher]

Increased female autosomal burden of rare copy number variants in human populations and in autism families.

January 15, 2015 - 8:46am
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Increased female autosomal burden of rare copy number variants in human populations and in autism families.

Mol Psychiatry. 2015 Jan 13;

Authors: Desachy G, Croen LA, Torres AR, Kharrazi M, Delorenze GN, Windham GC, Yoshida CK, Weiss LA

Abstract
Autosomal genetic variation is presumed equivalent in males and females and makes a major contribution to disease risk. We set out to identify whether maternal copy number variants (CNVs) contribute to autism spectrum disorders (ASDs). Surprisingly, we observed a higher autosomal burden of large, rare CNVs in females in the population, reflected in, but not unique to, ASD families. Meta-analysis across control data sets confirms female excess in CNV number (P=2.1 × 10(-5)) and gene content (P=4.1 × 10(-3)). We additionally observed CNV enrichment in ASD mothers compared with control mothers (P=0.03). We speculate that tolerance for CNV burden contributes to decreased female fetal loss in the population and that ASD-specific maternal CNV burden may contribute to high sibling recurrence. These data emphasize the need for study of familial CNV risk factors in ASDs and the requirement of sex-matched comparisons.Molecular Psychiatry advance online publication, 13 January 2015; doi:10.1038/mp.2014.179.

PMID: 25582617 [PubMed - as supplied by publisher]

Rare mutations of CACNB2 found in autism spectrum disease-affected families alter calcium channel function.

January 15, 2015 - 8:46am
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Rare mutations of CACNB2 found in autism spectrum disease-affected families alter calcium channel function.

PLoS One. 2014;9(4):e95579

Authors: Breitenkamp AF, Matthes J, Nass RD, Sinzig J, Lehmkuhl G, Nürnberg P, Herzig S

Abstract
Autism Spectrum Disorders (ASD) are complex neurodevelopmental diseases clinically defined by dysfunction of social interaction. Dysregulation of cellular calcium homeostasis might be involved in ASD pathogenesis, and genes coding for the L-type calcium channel subunits CaV1.2 (CACNA1C) and CaVβ2 (CACNB2) were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of CACNB2 (G167S, S197F, and F240L) found in ASD-affected families, two of them described here for the first time (G167S and F240L). All these mutations affect highly conserved regions while being absent in a sample of ethnically matched controls. We suggest the mutations to be of physiological relevance since they modulate whole-cell Ba2+ currents through calcium channels when expressed in a recombinant system (HEK-293 cells). Two mutations displayed significantly decelerated time-dependent inactivation as well as increased sensitivity of voltage-dependent inactivation. In contrast, the third mutation (F240L) showed significantly accelerated time-dependent inactivation. By altering the kinetic parameters, the mutations are reminiscent of the CACNA1C mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare CACNB2 missense mutations identified in ASD patients support the hypothesis that calcium channel dysfunction may contribute to autism.

PMID: 24752249 [PubMed - indexed for MEDLINE]

Autism traits in children and adolescents with Cornelia de Lange syndrome.

January 15, 2015 - 8:46am
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Autism traits in children and adolescents with Cornelia de Lange syndrome.

Am J Med Genet A. 2014 Jun;164A(6):1400-10

Authors: Srivastava S, Landy-Schmitt C, Clark B, Kline AD, Specht M, Grados MA

Abstract
Cornelia de Lange syndrome (CdLS) is a cohesinopathy causing delayed growth and limb deficits. Individuals with CdLS have mild to profound intellectual disability and autistic features. This study characterizes the behavioral phenotype of children with CdLS, focusing on autistic features, maladaptive behaviors, and impact of age. Children with CdLS (5-18 years) were administered normed instruments to characterize autism features (Childhood Autism Rating Scale, CARS), maladaptive behaviors (Aberrant Behavior Checklist), and adaptive skills (Vineland Adaptive Behaviors Scales). CdLS features and severity were rated with Diagnostic Criteria for CdLS. Forty-one children with CdLS (23 females, 18 males) were classified as having "no autism" (n = 7; 17.1%), "mild autism" (n = 17; 41.4%), and "severe autism" (n = 17; 41.4%), using CARS scores. Characteristic items were abnormal emotional response, stereotypies, odd object use, rigidity, lack of verbal communication, and low intellectual functioning. Verbal communication deficits and repetitive behaviors were higher compared to sensory, social cognition, and behavior abnormalities (P ≤ 0.0001). Maladaptive behaviors associated with autism traits were stereotypies (P = 0.003), hyperactivity (P = 0.01), and lethargy (P = 0.03). Activities of daily living were significantly affected; socialization adaptive skills were a relative strength. However, with advancing age, both socialization (P < 0.0001) and communication (P = 0.001) domains declined significantly. CdLS is characterized by autistic features, notably excessive repetitive behaviors and expressive language deficits. While other adaptive skills are impacted, socialization adaptive skills are less affected. Advancing age can worsen communication and socialization deficits relative to neurotypical peers.

PMID: 24718998 [PubMed - indexed for MEDLINE]

Outfoxed by RBFOX1-a caution about ascertainment bias.

January 15, 2015 - 8:46am
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Outfoxed by RBFOX1-a caution about ascertainment bias.

Am J Med Genet A. 2014 Jun;164A(6):1411-8

Authors: Kamien B, Lionel AC, Bain N, Scherer SW, Hunter M

Abstract
We report on two patients with intragenic deletions of RBFOX1 and one patient with an intragenic duplication of RBFOX1. These patients, by report, all had autism spectrum disorder and/or developmental delay and had strong family histories of these conditions. We initially hypothesized that RBFOX1 was another susceptibility locus for autism spectrum disorder or developmental delay. However, epidemiological evidence examining large numbers of individuals did not support this hypothesis and the data presented here suggests that RBFOX1 intragenic copy number variants are not pathogenic. This contradicts previous reports that examined smaller numbers of patients and controls. © 2014 Wiley Periodicals, Inc.

PMID: 24664471 [PubMed - indexed for MEDLINE]

Transient DNMT1 suppression reveals hidden heritable marks in the genome.

January 13, 2015 - 7:29am

Transient DNMT1 suppression reveals hidden heritable marks in the genome.

Nucleic Acids Res. 2015 Jan 10;

Authors: McGraw S, Zhang JX, Farag M, Chan D, Caron M, Konermann C, Oakes CC, Mohan KN, Plass C, Pastinen T, Bourque G, Chaillet JR, Trasler JM

Abstract
Genome-wide demethylation and remethylation of DNA during early embryogenesis is essential for development. Imprinted germline differentially methylated domains (gDMDs) established by sex-specific methylation in either male or female germ cells, must escape these dynamic changes and sustain precise inheritance of both methylated and unmethylated parental alleles. To identify other, gDMD-like sequences with the same epigenetic inheritance properties, we used a modified embryonic stem (ES) cell line that emulates the early embryonic demethylation and remethylation waves. Transient DNMT1 suppression revealed gDMD-like sequences requiring continuous DNMT1 activity to sustain a highly methylated state. Remethylation of these sequences was also compromised in vivo in a mouse model of transient DNMT1 loss in the preimplantation embryo. These novel regions, possessing heritable epigenetic features similar to imprinted-gDMDs are required for normal physiological and developmental processes and when disrupted are associated with disorders such as cancer and autism spectrum disorders. This study presents new perspectives on DNA methylation heritability during early embryo development that extend beyond conventional imprinted-gDMDs.

PMID: 25578964 [PubMed - as supplied by publisher]

Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): Recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement.

January 13, 2015 - 7:29am

Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): Recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement.

Res Dev Disabil. 2015 Jan 6;38C:242-255

Authors: Guinchat V, Cravero C, Diaz L, Périsse D, Xavier J, Amiet C, Gourfinkel-An I, Bodeau N, Wachtel L, Cohen D, Consoli A

Abstract
During adolescence, some individuals with autism spectrum disorder (ASD) engage in severe challenging behaviors, such as aggression, self-injury, disruption, agitation and tantrums. We aimed to assess risk factors associated with very acute behavioral crises in adolescents with ASD admitted to a dedicated neurobehavioral unit. We included retrospectively in 2008 and 2009 29 adolescents and young adults with ASD hospitalized for severe challenging behaviors and proposed a guideline (Perisse et al., 2010) that we applied prospectively for 29 patients recruited for the same indications between 2010 and 2012. In total, 58 patients were admitted (n=70 hospitalizations, mean age=15.66 (±4.07) years, 76% male). We systematically collected data describing socio-demographic characteristics, clinical variables (severity, presence of language, cognitive level), comorbid organic conditions, etiologic diagnosis of the episode, and treatments. We explored predictors of Global Assessment Functioning Scale (GAFS) score and duration of hospitalization at discharge. All but 2 patients exhibited severe autistic symptoms and intellectual disability (ID), and two-thirds had no functional verbal language. During the inpatient stay (mean=84.3 (±94.9) days), patients doubled on average their GAFS scores (mean=17.66 (±9.05) at admission vs. mean=31.4 (±9.48) at discharge). Most common etiologies for acute behavioral crises were organic causes [n=20 (28%), including epilepsy: n=10 (14%) and painful medical conditions: n=10 (14%)], environmental causes [n=17 (25%) including lack of treatment: n=11 (16%) and adjustment disorder: n=6 (9%)], and non-ASD psychiatric condition [n=33 (48%) including catatonia: n=5 (7%), major depressive episode: n=6 (9%), bipolar disorder: n=4 (6%), schizophrenia: n=6 (9%), other/unknown diagnosis: n=12 (17%)]. We found no influence of age, gender, socio-economic status, migration, level of ID, or history of seizure on improvement of GAFS score at discharge. Severity of autism at admission was the only negative predictor (p<.001). Painful medical conditions (p=.04), non-ASD psychiatric diagnoses (p=.001), prior usage of specialized ASD care programs (p=.004), functional language (p=.007), as well as a higher number of challenging behaviors upon admission (p=.001) were associated with higher GAFS scores at discharge. Clinical severity at admission, based on the number of challenging behaviors (r=.35, p=.003) and GAFS score (r=-.32, p=.008) was correlated with a longer inpatient stay. Longer hospitalization was however correlated (r=.27, p=.03) with higher GAFS score at discharge even after adjustment for confounding factors. Challenging behaviors among adolescents with ASD may stem from diverse risk factors, including environmental problems, comorbid acute psychiatric conditions, or somatic illness such as epilepsy or acute pain. The management of these behavioral challenges requires a unified, multidisciplinary approach.

PMID: 25575287 [PubMed - as supplied by publisher]

Whole exome sequencing in females with autism implicates novel and candidate genes.

January 13, 2015 - 7:29am

Whole exome sequencing in females with autism implicates novel and candidate genes.

Int J Mol Sci. 2015;16(1):1312-35

Authors: Butler MG, Rafi SK, Hossain W, Stephan DA, Manzardo AM

Abstract
Classical autism or autistic disorder belongs to a group of genetically heterogeneous conditions known as Autism Spectrum Disorders (ASD). Heritability is estimated as high as 90% for ASD with a recently reported compilation of 629 clinically relevant candidate and known genes. We chose to undertake a descriptive next generation whole exome sequencing case study of 30 well-characterized Caucasian females with autism (average age, 7.7 ± 2.6 years; age range, 5 to 16 years) from multiplex families. Genomic DNA was used for whole exome sequencing via paired-end next generation sequencing approach and X chromosome inactivation status. The list of putative disease causing genes was developed from primary selection criteria using machine learning-derived classification score and other predictive parameters (GERP2, PolyPhen2, and SIFT). We narrowed the variant list to 10 to 20 genes and screened for biological significance including neural development, function and known neurological disorders. Seventy-eight genes identified met selection criteria ranging from 1 to 9 filtered variants per female. Five females presented with functional variants of X-linked genes (IL1RAPL1, PIR, GABRQ, GPRASP2, SYTL4) with cadherin, protocadherin and ankyrin repeat gene families most commonly altered (e.g., CDH6, FAT2, PCDH8, CTNNA3, ANKRD11). Other genes related to neurogenesis and neuronal migration (e.g., SEMA3F, MIDN), were also identified.

PMID: 25574603 [PubMed - in process]

Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase.

January 13, 2015 - 7:29am
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Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase.

Nat Neurosci. 2014 Nov;17(11):1583-90

Authors: Molosh AI, Johnson PL, Spence JP, Arendt D, Federici LM, Bernabe C, Janasik SP, Segu ZM, Khanna R, Goswami C, Zhu W, Park SJ, Li L, Mechref YS, Clapp DW, Shekhar A

Abstract
Children with neurofibromatosis type 1 (NF1) are increasingly recognized as having a high prevalence of social difficulties and autism spectrum disorders (ASDs). We demonstrated a selective social learning deficit in mice with deletion of a single Nf1 allele (Nf1(+/-)), along with greater activation of the mitogen-activated protein kinase pathway in neurons from the amygdala and frontal cortex, structures that are relevant to social behaviors. The Nf1(+/-) mice showed aberrant amygdala glutamate and GABA neurotransmission, deficits in long-term potentiation and specific disruptions in the expression of two proteins that are associated with glutamate and GABA neurotransmission: a disintegrin and metalloprotease domain 22 (Adam22) and heat shock protein 70 (Hsp70), respectively. All of these amygdala disruptions were normalized by the additional deletion of the p21 protein-activated kinase (Pak1) gene. We also rescued the social behavior deficits in Nf1(+/-) mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide insights and therapeutic targets for patients with NF1 and ASDs.

PMID: 25242307 [PubMed - indexed for MEDLINE]

Most genetic risk for autism resides with common variation.

January 13, 2015 - 7:29am
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Most genetic risk for autism resides with common variation.

Nat Genet. 2014 Aug;46(8):881-5

Authors: Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CM, Devlin B, Roeder K, Buxbaum JD

Abstract
A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. Individual risk-associated genes have been identified from rare variation, especially de novo mutations. From this evidence, one might conclude that rare variation dominates the allelic spectrum in autism, yet recent studies show that common variation, individually of small effect, has substantial impact en masse. At issue is how much of an impact relative to rare variation this common variation has. Using a unique epidemiological sample from Sweden, new methods that distinguish total narrow-sense heritability from that due to common variation and synthesis of results from other studies, we reach several conclusions about autism's genetic architecture: its narrow-sense heritability is ∼52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation.

PMID: 25038753 [PubMed - indexed for MEDLINE]

The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta).

January 13, 2015 - 7:29am
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The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta).

Psychoneuroendocrinology. 2014 Jul;45:128-41

Authors: Freeman SM, Inoue K, Smith AL, Goodman MM, Young LJ

Abstract
The rhesus macaque (Macaca mulatta) is an important primate model for social cognition, and recent studies have begun to explore the impact of oxytocin on social cognition and behavior. Macaques have great potential for elucidating the neural mechanisms by which oxytocin modulates social cognition, which has implications for oxytocin-based pharmacotherapies for psychiatric disorders such as autism and schizophrenia. Previous attempts to localize oxytocin receptors (OXTR) in the rhesus macaque brain have failed due to reduced selectivity of radioligands, which in primates bind to both OXTR and the structurally similar vasopressin 1a receptor (AVPR1A). We have developed a pharmacologically-informed competitive binding autoradiography protocol that selectively reveals OXTR and AVPR1A binding sites in primate brain sections. Using this protocol, we describe the neuroanatomical distribution of OXTR in the macaque. Finally, we use in situ hybridization to localize OXTR mRNA. Our results demonstrate that OXTR expression in the macaque brain is much more restricted than AVPR1A. OXTR is largely limited to the nucleus basalis of Meynert, pedunculopontine tegmental nucleus, the superficial gray layer of the superior colliculus, the trapezoid body, and the ventromedial hypothalamus. These regions are involved in a variety of functions relevant to social cognition, including modulating visual attention, processing auditory and multimodal sensory stimuli, and controlling orienting responses to visual stimuli. These results provide insights into the neural mechanisms by which oxytocin modulates social cognition and behavior in this species, which, like humans, uses vision and audition as the primary modalities for social communication.

PMID: 24845184 [PubMed - indexed for MEDLINE]

A genome wide association study of mathematical ability reveals an association at chromosome 3q29, a locus associated with autism and learning difficulties: a preliminary study.

January 13, 2015 - 7:29am
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A genome wide association study of mathematical ability reveals an association at chromosome 3q29, a locus associated with autism and learning difficulties: a preliminary study.

PLoS One. 2014;9(5):e96374

Authors: Baron-Cohen S, Murphy L, Chakrabarti B, Craig I, Mallya U, Lakatošová S, Rehnstrom K, Peltonen L, Wheelwright S, Allison C, Fisher SE, Warrier V

Abstract
Mathematical ability is heritable, but few studies have directly investigated its molecular genetic basis. Here we aimed to identify specific genetic contributions to variation in mathematical ability. We carried out a genome wide association scan using pooled DNA in two groups of U.K. samples, based on end of secondary/high school national academic exam achievement: high (n = 419) versus low (n = 183) mathematical ability while controlling for their verbal ability. Significant differences in allele frequencies between these groups were searched for in 906,600 SNPs using the Affymetrix GeneChip Human Mapping version 6.0 array. After meeting a threshold of p<1.5×10(-5), 12 SNPs from the pooled association analysis were individually genotyped in 542 of the participants and analyzed to validate the initial associations (lowest p-value 1.14 ×10(-6)). In this analysis, one of the SNPs (rs789859) showed significant association after Bonferroni correction, and four (rs10873824, rs4144887, rs12130910 rs2809115) were nominally significant (lowest p-value 3.278 × 10(-4)). Three of the SNPs of interest are located within, or near to, known genes (FAM43A, SFT2D1, C14orf64). The SNP that showed the strongest association, rs789859, is located in a region on chromosome 3q29 that has been previously linked to learning difficulties and autism. rs789859 lies 1.3 kbp downstream of LSG1, and 700 bp upstream of FAM43A, mapping within the potential promoter/regulatory region of the latter. To our knowledge, this is only the second study to investigate the association of genetic variants with mathematical ability, and it highlights a number of interesting markers for future study.

PMID: 24801482 [PubMed - indexed for MEDLINE]

De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability.

January 13, 2015 - 7:29am
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De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability.

Mol Psychiatry. 2014 Jun;19(6):652-8

Authors: McCarthy SE, Gillis J, Kramer M, Lihm J, Yoon S, Berstein Y, Mistry M, Pavlidis P, Solomon R, Ghiban E, Antoniou E, Kelleher E, O'Brien C, Donohoe G, Gill M, Morris DW, McCombie WR, Corvin A

Abstract
Schizophrenia is a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNMs) in schizophrenia and autism have reinforced the hypothesis that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familial schizophrenia. In sporadic trios, we observed a ~3.5-fold increase in the proportion of nonsense DNMs (0.101 vs 0.031, empirical P=0.01, Benjamini-Hochberg-corrected P=0.044). These mutations were significantly more likely to occur in genes with highly ranked probabilities of haploinsufficiency (P=0.0029, corrected P=0.006). DNMs of potential functional consequence were also found to occur in genes predicted to be less tolerant to rare variation (P=2.01 × 10(-)(5), corrected P=2.1 × 10(-)(3)). Genes with DNMs overlapped with genes implicated in autism (for example, AUTS2, CHD8 and MECP2) and intellectual disability (for example, HUWE1 and TRAPPC9), supporting a shared genetic etiology between these disorders. Functionally CHD8, MECP2 and HUWE1 converge on epigenetic regulation of transcription suggesting that this may be an important risk mechanism. Our results were consistent in an analysis of additional exome-based sequencing studies of other neurodevelopmental disorders. These findings suggest that perturbations in genes, which function in the epigenetic regulation of brain development and cognition, could have a central role in the susceptibility to, pathogenesis and treatment of mental disorders.

PMID: 24776741 [PubMed - indexed for MEDLINE]

Autistic children display elevated urine levels of bovine casomorphin-7 immunoreactivity.

January 13, 2015 - 7:29am
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Autistic children display elevated urine levels of bovine casomorphin-7 immunoreactivity.

Peptides. 2014 Jun;56:68-71

Authors: Sokolov O, Kost N, Andreeva O, Korneeva E, Meshavkin V, Tarakanova Y, Dadayan A, Zolotarev Y, Grachev S, Mikheeva I, Varlamov O, Zozulya A

Abstract
Elevated concentrations of circulating casomorphins (CM), the exogenous opioid peptides from milk casein, may contribute to the pathogenesis of autism in children. Because several mass spectrometry studies failed to detect casomorphins in autistic children, it was questioned whether these peptides can be detected in body fluids by mass spec. Here we demonstrated, using a novel high sensitivity ELISA method, that autistic children have significantly higher levels of urine CM-7 than control children. The severity of autistic symptoms correlated with concentrations of CM-7 in the urine. Because CMs interact with opioid and serotonin receptors, the known modulators of synaptogenesis, we suggest that chronic exposure to elevated levels of bovine CMs may impair early child development, setting the stage for autistic disorders.

PMID: 24657283 [PubMed - indexed for MEDLINE]

Absence of strong strain effects in behavioral analyses of Shank3-deficient mice.

January 13, 2015 - 7:29am
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Absence of strong strain effects in behavioral analyses of Shank3-deficient mice.

Dis Model Mech. 2014 Jun;7(6):667-81

Authors: Drapeau E, Dorr NP, Elder GA, Buxbaum JD

Abstract
Haploinsufficiency of SHANK3, caused by chromosomal abnormalities or mutations that disrupt one copy of the gene, leads to a neurodevelopmental syndrome called Phelan-McDermid syndrome, symptoms of which can include absent or delayed speech, intellectual disability, neurological changes and autism spectrum disorders. The SHANK3 protein forms a key structural part of the post-synaptic density. We previously generated and characterized mice with a targeted disruption of Shank3 in which exons coding for the ankyrin-repeat domain were deleted and expression of full-length Shank3 was disrupted. We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions, in Shank3 heterozygous mice. Changes in phenotype owing to a mutation at a single locus are quite frequently modulated by other loci, most dramatically when the entire genetic background is changed. In mice, each strain of laboratory mouse represents a distinct genetic background and alterations in phenotype owing to gene knockout or transgenesis are frequently different across strains, which can lead to the identification of important modifier loci. We have investigated the effect of genetic background on phenotypes of Shank3 heterozygous, knockout and wild-type mice, using C57BL/6, 129SVE and FVB/Ntac strain backgrounds. We focused on observable behaviors with the goal of carrying out subsequent analyses to identify modifier loci. Surprisingly, there were very modest strain effects over a large battery of analyses. These results indicate that behavioral phenotypes associated with Shank3 haploinsufficiency are largely strain-independent.

PMID: 24652766 [PubMed - indexed for MEDLINE]

Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production.

January 13, 2015 - 7:29am
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Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production.

Hum Mol Genet. 2014 Jun 15;23(12):3212-27

Authors: Tilot AK, Gaugler MK, Yu Q, Romigh T, Yu W, Miller RH, Frazier TW, Eng C

Abstract
PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal-dominant genetic condition underlying a subset of autism spectrum disorder (ASD) with macrocephaly. Caused by germline mutations in PTEN, PHTS also causes increased risks of multiple cancers via dysregulation of the PI3K and MAPK signaling pathways. Conditional knockout models have shown that neural Pten regulates social behavior, proliferation and cell size. Although much is known about how the intracellular localization of PTEN regulates signaling in cancer cell lines, we know little of how PTEN localization influences normal brain physiology and behavior. To address this, we generated a germline knock-in mouse model of cytoplasm-predominant Pten and characterized its behavioral and cellular phenotypes. The homozygous Pten(m3m4) mice have decreased total Pten levels including a specific drop in nuclear Pten and exhibit region-specific increases in brain weight. The Pten(m3m4) model displays sex-specific increases in social motivation, poor balance and normal recognition memory-a profile reminiscent of some individuals with high functioning ASD. The cytoplasm-predominant protein caused cellular hypertrophy limited to the soma and led to increased NG2 cell proliferation and accumulation of glia. The animals also exhibit significant astrogliosis and microglial activation, indicating a neuroinflammatory phenotype. At the signaling level, Pten(m3m4) mice show brain region-specific differences in Akt activation. These results demonstrate that differing alterations to the same autism-linked gene can cause distinct behavioral profiles. The Pten(m3m4) model is the first murine model of inappropriately elevated social motivation in the context of normal cognition and may expand the range of autism-related behaviors replicated in animal models.

PMID: 24470394 [PubMed - indexed for MEDLINE]

CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size.

January 13, 2015 - 7:29am
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CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size.

Hum Mol Genet. 2014 Jun 15;23(12):3228-38

Authors: Ludwig AL, Espinal GM, Pretto DI, Jamal AL, Arque G, Tassone F, Berman RF, Hagerman PJ

Abstract
Large expansions of a CGG-repeat element (>200 repeats; full mutation) in the fragile X mental retardation 1 (FMR1) gene cause fragile X syndrome (FXS), the leading single-gene form of intellectual disability and of autism spectrum disorder. Smaller expansions (55-200 CGG repeats; premutation) result in the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Whereas FXS is caused by gene silencing and insufficient FMR1 protein (FMRP), FXTAS is thought to be caused by 'toxicity' of expanded-CGG-repeat mRNA. However, as FMRP expression levels decrease with increasing CGG-repeat length, lowered protein may contribute to premutation-associated clinical involvement. To address this issue, we measured brain Fmr1 mRNA and FMRP levels as a function of CGG-repeat length in a congenic (CGG-repeat knock-in) mouse model using 57 wild-type and 97 expanded-CGG-repeat mice carrying up to ~250 CGG repeats. While Fmr1 message levels increased with repeat length, FMRP levels trended downward over the same range, subject to significant inter-subject variation. Human comparisons of protein levels in the frontal cortex of 7 normal and 17 FXTAS individuals revealed that the mild FMRP decrease in mice mirrored the more limited data for FMRP expression in the human samples. In addition, FMRP expression levels varied in a subset of mice across the cerebellum, frontal cortex, and hippocampus, as well as at different ages. These results provide a foundation for understanding both the CGG-repeat-dependence of FMRP expression and for interpreting clinical phenotypes in premutation carriers in terms of the balance between elevated mRNA and lowered FMRP expression levels.

PMID: 24463622 [PubMed - indexed for MEDLINE]

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