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Next-generation sequencing in schizophrenia and other neuropsychiatric disorders.

May 28, 2014 - 7:53am
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Next-generation sequencing in schizophrenia and other neuropsychiatric disorders.

Am J Med Genet B Neuropsychiatr Genet. 2013 Oct;162B(7):671-8

Authors: Schreiber M, Dorschner M, Tsuang D

Abstract
Schizophrenia is a debilitating lifelong illness that lacks a cure and poses a worldwide public health burden. The disease is characterized by a heterogeneous clinical and genetic presentation that complicates research efforts to identify causative genetic variations. This review examines the potential of current findings in schizophrenia and in other related neuropsychiatric disorders for application in next-generation technologies, particularly whole-exome sequencing (WES) and whole-genome sequencing (WGS). These approaches may lead to the discovery of underlying genetic factors for schizophrenia and may thereby identify and target novel therapeutic targets for this devastating disorder.

PMID: 24132899 [PubMed - indexed for MEDLINE]

Rare deleterious mutations of the gene EFR3A in autism spectrum disorders.

May 27, 2014 - 7:26am

Rare deleterious mutations of the gene EFR3A in autism spectrum disorders.

Mol Autism. 2014;5:31

Authors: Gupta AR, Pirruccello M, Cheng F, Kang HJ, Fernandez TV, Baskin JM, Choi M, Liu L, Ercan-Sencicek AG, Murdoch JD, Klei L, Neale BM, Franjic D, Daly MJ, Lifton RP, De Camilli P, Zhao H, Sestan N, State MW

Abstract
BACKGROUND: Whole-exome sequencing studies in autism spectrum disorder (ASD) have identified de novo mutations in novel candidate genes, including the synaptic gene Eighty-five Requiring 3A (EFR3A). EFR3A is a critical component of a protein complex required for the synthesis of the phosphoinositide PtdIns4P, which has a variety of functions at the neural synapse. We hypothesized that deleterious mutations in EFR3A would be significantly associated with ASD.
METHODS: We conducted a large case/control association study by deep resequencing and analysis of whole-exome data for coding and splice site variants in EFR3A. We determined the potential impact of these variants on protein structure and function by a variety of conservation measures and analysis of the Saccharomyces cerevisiae Efr3 crystal structure. We also analyzed the expression pattern of EFR3A in human brain tissue.
RESULTS: Rare nonsynonymous mutations in EFR3A were more common among cases (16 / 2,196 = 0.73%) than matched controls (12 / 3,389 = 0.35%) and were statistically more common at conserved nucleotides based on an experiment-wide significance threshold (P = 0.0077, permutation test). Crystal structure analysis revealed that mutations likely to be deleterious were also statistically more common in cases than controls (P = 0.017, Fisher exact test). Furthermore, EFR3A is expressed in cortical neurons, including pyramidal neurons, during human fetal brain development in a pattern consistent with ASD-related genes, and it is strongly co-expressed (P < 2.2 × 10(-16), Wilcoxon test) with a module of genes significantly associated with ASD.
CONCLUSIONS: Rare deleterious mutations in EFR3A were found to be associated with ASD using an experiment-wide significance threshold. Synaptic phosphoinositide metabolism has been strongly implicated in syndromic forms of ASD. These data for EFR3A strengthen the evidence for the involvement of this pathway in idiopathic autism.

PMID: 24860643 [PubMed]

Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder.

May 27, 2014 - 7:26am

Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder.

Nat Genet. 2014 May 25;

Authors: Uddin M, Tammimies K, Pellecchia G, Alipanahi B, Hu P, Wang Z, Pinto D, Lau L, Nalpathamkalam T, Marshall CR, Blencowe BJ, Frey BJ, Merico D, Yuen RK, Scherer SW

Abstract
A universal challenge in genetic studies of autism spectrum disorders (ASDs) is determining whether a given DNA sequence alteration will manifest as disease. Among different population controls, we observed, for specific exons, an inverse correlation between exon expression level in brain and burden of rare missense mutations. For genes that harbor de novo mutations predicted to be deleterious, we found that specific critical exons were significantly enriched in individuals with ASD relative to their siblings without ASD (P < 1.13 × 10(-38); odds ratio (OR) = 2.40). Furthermore, our analysis of genes with high exonic expression in brain and low burden of rare mutations demonstrated enrichment for known ASD-associated genes (P < 3.40 × 10(-11); OR = 6.08) and ASD-relevant fragile-X protein targets (P < 2.91 × 10(-157); OR = 9.52). Our results suggest that brain-expressed exons under purifying selection should be prioritized in genotype-phenotype studies for ASD and related neurodevelopmental conditions.

PMID: 24859339 [PubMed - as supplied by publisher]

Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with autism spectrum disorder.

May 27, 2014 - 7:26am
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Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with autism spectrum disorder.

PLoS One. 2013;8(9):e74167

Authors: Koshimizu E, Miyatake S, Okamoto N, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Matsumoto N

Abstract
Next-generation sequencing (NGS) combined with enrichment of target genes enables highly efficient and low-cost sequencing of multiple genes for genetic diseases. The aim of this study was to validate the accuracy and sensitivity of our method for comprehensive mutation detection in autism spectrum disorder (ASD). We assessed the performance of the bench-top Ion Torrent PGM and Illumina MiSeq platforms as optimized solutions for mutation detection, using microdroplet PCR-based enrichment of 62 ASD associated genes. Ten patients with known mutations were sequenced using NGS to validate the sensitivity of our method. The overall read quality was better with MiSeq, largely because of the increased indel-related error associated with PGM. The sensitivity of SNV detection was similar between the two platforms, suggesting they are both suitable for SNV detection in the human genome. Next, we used these methods to analyze 28 patients with ASD, and identified 22 novel variants in genes associated with ASD, with one mutation detected by MiSeq only. Thus, our results support the combination of target gene enrichment and NGS as a valuable molecular method for investigating rare variants in ASD.

PMID: 24066114 [PubMed - indexed for MEDLINE]

CYP1A2 polymorphisms in slow melatonin metabolisers: a possible relationship with autism spectrum disorder?

May 27, 2014 - 7:26am
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CYP1A2 polymorphisms in slow melatonin metabolisers: a possible relationship with autism spectrum disorder?

J Intellect Disabil Res. 2013 Nov;57(11):993-1000

Authors: Braam W, Keijzer H, Struijker Boudier H, Didden R, Smits M, Curfs L

Abstract
BACKGROUND: In some of our patients with intellectual disabilities (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment. In these patients melatonin levels at noon were extremely high (>50 pg/ml). We hypothesise that the disappearing effectiveness is associated with slow metabolisation of melatonin because of a single nucleotide polymorphism (SNP) of CYP1A2.
METHOD: In this pilot study we analysed DNA extracted from saliva samples of 15 consecutive patients with disappearing effectiveness of melatonin. Saliva was collected at noon and 4 pm for measuring melatonin levels.
RESULTS: In all patients' salivary melatonin levels at noon were >50 or melatonin half time was > 5 h. A SNP was found in eight of 15 patients. The allele 1C was found in two patients and in six patients the 1F allele was found.
CONCLUSIONS: Of 15 patients with disappearing effectiveness of melatonin, seven were diagnosed with autism spectrum disorder, and in four of them a SNP was found. The other eight patients were known with a genetic syndrome. In six of them behaviour was considered to be autistic-type and in three of them a SNP was found. This finding may give a new direction for research into the genetic background of autism.

PMID: 22823064 [PubMed - indexed for MEDLINE]

Autism spectrum disorders and hyperactive/impulsive behaviors in Japanese patients with Prader-Willi syndrome: A comparison between maternal uniparental disomy and deletion cases.

May 23, 2014 - 8:51am

Autism spectrum disorders and hyperactive/impulsive behaviors in Japanese patients with Prader-Willi syndrome: A comparison between maternal uniparental disomy and deletion cases.

Am J Med Genet A. 2014 May 21;

Authors: Ogata H, Ihara H, Murakami N, Gito M, Kido Y, Nagai T

Abstract
This study aims to compare maternal uniparental disomy 15 (mUPD) and a paternal deletion of 15q11-13 (DEL) of Prader-Willi syndrome (PWS) in regard to autism spectrum disorders (ASD). Forty-five Japanese individuals with PWS were recruited from a single recruitment center. The participants consisted of 22 children (aged from 6 to 12) and 23 adolescents (aged from 13 to 19). Six children and seven adolescents were confirmed as having mUPD. Sixteen children and 16 adolescents were confirmed as having DEL. Under blindness to the participants' genotypes, a single psychologist carried out behavioral and psychological assessments, including the Wechsler Intelligence Scales, Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS), and ADHD-Rating Scale-IV (ADHD-RS-IV). Two comparisons were made: one between mUPD and DEL children and another between mUPD and DEL adolescents. In children, no significant differences were found between mUPD and DEL participants in terms of autistic (PARS childhood, P = 0.657) and impulsive behaviors (ADHD-RS-IV hyperactive/impulsive, P = 0.275). In adolescents, mUPD patients showed significantly more autistic symptomatology (PARS adolescent, P = 0.027) and significantly more impulsive behavior (ADHD-RS-IV hyperactive/impulsive, P = 0.01) than DEL patients. Our findings about Japanese PWS patients were consistent with previous researches from western countries not focused on Asian patients, indicating that mUPD cases would be more prone to ASD than DEL cases, regardless of ethnoregional differences. In addition, our data suggested that the behavioral difference between mUPD and DEL cases in terms of autistic and impulsive symptoms tend to be unrecognizable in their childhood. © 2014 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

PMID: 24850752 [PubMed - as supplied by publisher]

No increase in autism-associated genetic events in children conceived by assisted reproduction.

May 21, 2014 - 8:12am

No increase in autism-associated genetic events in children conceived by assisted reproduction.

Fertil Steril. 2014 May 17;

Authors: Ackerman S, Wenegrat J, Rettew D, Althoff R, Bernier R

Abstract
OBJECTIVE: To understand the rate of genetic events in patients with autism spectrum disorder (ASD) who were exposed to assisted reproduction.
DESIGN: Case control study using genetics data.
SETTING: Twelve collaborating data collection sites across North America as part of the Simons Simplex Collection.
PATIENT(S): 2,760 children with ASD, for whom 1,994 had published copy number variation data and 424 had published gene mutation status available.
INTERVENTION(S): None.
MAIN OUTCOME MEASURE(S): Rates of autism-associated genetic events in children with ASD conceived with assisted reproduction versus those conceived naturally.
RESULT(S): No statistically significant differences in copy number variations or autism-associated gene-disrupting events were found when comparing ASD patients exposed to assisted reproduction with those not exposed to assisted reproduction.
CONCLUSION(S): This is the first large genetic association to concurrently examine the genotype of individuals with ASD in relation to their exposure to ART versus natural conception, and it adds reassuring evidence to the argument that ART does not increase the risk of ASD.

PMID: 24842673 [PubMed - as supplied by publisher]

Maternal inflammation promotes fetal microglial activation and increased cholinergic expression in the fetal basal forebrain: role of interleukin-6.

May 20, 2014 - 7:55am
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Maternal inflammation promotes fetal microglial activation and increased cholinergic expression in the fetal basal forebrain: role of interleukin-6.

Pediatr Res. 2013 Oct;74(4):393-401

Authors: Pratt L, Ni L, Ponzio NM, Jonakait GM

Abstract
BACKGROUND: Perinatal exposure to infectious agents with associated maternal immune activation (MIA) leads to neuroanatomical and behavioral dysregulation reminiscent of autism spectrum disorders. Persistent microglial activation as well as increased choline acetyltransferase (ChAT) activity in the basal forebrain (BF) are characteristic of autistic subjects. Previous studies have shown that medium from activated microglia promotes cholinergic differentiation of precursors in the BF. We sought to determine whether MIA in vivo would lead to a similar effect on developing BF neurons.
METHODS: Pregnant mice were treated with the viral mimic polyinosinic-polycytidylic acid (poly(I:C)) or saline.
RESULTS: Poly(I:C) treatment resulted in increased production of cytokines and chemokines in fetal microglia and increased ChAT activity and cholinergic cell number in the perinatal BF. Whether microglial activation causes these changes is unclear. Examination of fetal brains from mice lacking interleukin-6 (IL-6 KOs) revealed an elevation in non-microglial-derived cytokines and chemokines over wild-type controls. Moreover, IL-6 KO offspring showed an elevation of ChAT activity even in the absence of poly(I:C) administration.
CONCLUSION: These data suggest that elevations in cytokines and/or chemokines caused either by maternal poly(I:C) administration or by the absence of IL-6 are associated with alterations in cholinergic development in the BF.

PMID: 23877071 [PubMed - indexed for MEDLINE]

Mutation screening in the Greek population and evaluation of NLGN3 and NLGN4X genes causal factors for autism.

May 20, 2014 - 7:55am
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Mutation screening in the Greek population and evaluation of NLGN3 and NLGN4X genes causal factors for autism.

Psychiatr Genet. 2013 Oct;23(5):198-203

Authors: Volaki K, Pampanos A, Kitsiou-Tzeli S, Vrettou C, Oikonomakis V, Sofocleous C, Kanavakis E

Abstract
Molecular and neurobiological evidence for the involvement of neuroligins (particularly NLGN3 and NLGN4X genes) in autistic disorder is accumulating. However, previous mutation screening studies on these two genes have yielded controversial results. The present study explores, for the first time, the contribution of NLGN3 and NLGN4X genetic variants in Greek patients with autistic disorder. We analyzed the full exonic sequence of NLGN3 and NLGN4X genes in 40 patients strictly fulfilling the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. criteria for autistic disorder. We identified nine nucleotide changes in NLGN4X--one probable causative mutation (p.K378R) previously reported by our research group, one novel variant (c.-206G>C), one nonvalidated single nucleotide polymorphism (SNP, rs111953947), and six known human SNPs reported in the SNP database--and one known human SNP in NLGN3 also reported in the SNP database. The variants identified are expected to be benign. However, they should be investigated in the context of variants in interacting cellular pathways to assess their contribution to the etiology of autism.

PMID: 23851596 [PubMed - indexed for MEDLINE]

CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems.

May 17, 2014 - 9:21am

CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems.

J Neurodev Disord. 2014;6(1):9

Authors: Chénier S, Yoon G, Argiropoulos B, Lauzon J, Laframboise R, Ahn JW, Ogilvie CM, Lionel AC, Marshall CR, Vaags AK, Hashemi B, Boisvert K, Mathonnet G, Tihy F, So J, Scherer SW, Lemyre E, Stavropoulos DJ

Abstract
BACKGROUND: The chromodomain helicase DNA binding domain (CHD) proteins modulate gene expression via their ability to remodel chromatin structure and influence histone acetylation. Recent studies have shown that CHD2 protein plays a critical role in embryonic development, tumor suppression and survival. Like other genes encoding members of the CHD family, pathogenic mutations in the CHD2 gene are expected to be implicated in human disease. In fact, there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders. Despite growing evidence, a description of the full phenotypic spectrum of this condition is lacking.
METHODS: We conducted a multicentre study to identify and characterise the clinical features associated with haploinsufficiency of CHD2. Patients with deletions of this gene were identified from among broadly ascertained clinical cohorts undergoing genomic microarray analysis for developmental delay, congenital anomalies and/or autism spectrum disorder.
RESULTS: Detailed clinical assessments by clinical geneticists showed recurrent clinical symptoms, including developmental delay, intellectual disability, epilepsy, behavioural problems and autism-like features without characteristic facial gestalt or brain malformations observed on magnetic resonance imaging scans. Parental analysis showed that the deletions affecting CHD2 were de novo in all four patients, and analysis of high-resolution microarray data derived from 26,826 unaffected controls showed no deletions of this gene.
CONCLUSIONS: The results of this study, in addition to our review of the literature, support a causative role of CHD2 haploinsufficiency in developmental delay, intellectual disability, epilepsy and behavioural problems, with phenotypic variability between individuals.

PMID: 24834135 [PubMed]

The familial risk of autism.

May 17, 2014 - 6:21am
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The familial risk of autism.

JAMA. 2014 May 7;311(17):1770-7

Authors: Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A

Abstract
IMPORTANCE: Autism spectrum disorder (ASD) aggregates in families, but the individual risk and to what extent this is caused by genetic factors or shared or nonshared environmental factors remains unresolved.
OBJECTIVE: To provide estimates of familial aggregation and heritability of ASD.
DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort including 2,049,973 Swedish children born 1982 through 2006. We identified 37,570 twin pairs, 2,642,064 full sibling pairs, 432,281 maternal and 445,531 paternal half sibling pairs, and 5,799,875 cousin pairs. Diagnoses of ASD to December 31, 2009 were ascertained.
MAIN OUTCOMES AND MEASURES: The relative recurrence risk (RRR) measures familial aggregation of disease. The RRR is the relative risk of autism in a participant with a sibling or cousin who has the diagnosis (exposed) compared with the risk in a participant with no diagnosed family member (unexposed). We calculated RRR for both ASD and autistic disorder adjusting for age, birth year, sex, parental psychiatric history, and parental age. We estimated how much of the probability of developing ASD can be related to genetic (additive and dominant) and environmental (shared and nonshared) factors.
RESULTS: In the sample, 14,516 children were diagnosed with ASD, of whom 5689 had autistic disorder. The RRR and rate per 100,000 person-years for ASD among monozygotic twins was estimated to be 153.0 (95% CI, 56.7-412.8; rate, 6274 for exposed vs 27 for unexposed ); for dizygotic twins, 8.2 (95% CI, 3.7-18.1; rate, 805 for exposed vs 55 for unexposed); for full siblings, 10.3 (95% CI, 9.4-11.3; rate, 829 for exposed vs 49 for unexposed); for maternal half siblings, 3.3 (95% CI, 2.6-4.2; rate, 492 for exposed vs 94 for unexposed); for paternal half siblings, 2.9 (95% CI, 2.2-3.7; rate, 371 for exposed vs 85 for unexposed); and for cousins, 2.0 (95% CI, 1.8-2.2; rate, 155 for exposed vs 49 for unexposed). The RRR pattern was similar for autistic disorder but of slightly higher magnitude.We found support for a disease etiology including only additive genetic and nonshared environmental effects. The ASD heritability was estimated to be 0.50 (95% CI, 0.45-0.56) and the autistic disorder heritability was estimated to 0.54 (95% CI, 0.44-0.64).
CONCLUSIONS AND RELEVANCE: Among children born in Sweden, the individual risk of ASD and autistic disorder increased with increasing genetic relatedness. Heritability of ASD and autistic disorder were estimated to be approximately 50%. These findings may inform the counseling of families with affected children.

PMID: 24794370 [PubMed - indexed for MEDLINE]

The genetic and environmental contributions to autism: looking beyond twins.

May 17, 2014 - 6:21am
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The genetic and environmental contributions to autism: looking beyond twins.

JAMA. 2014 May 7;311(17):1738-9

Authors: Schendel DE, Grønborg TK, Parner ET

PMID: 24794365 [PubMed - indexed for MEDLINE]

MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex.

May 17, 2014 - 6:21am
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MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex.

Dev Cell. 2014 Mar 10;28(5):547-60

Authors: Cheng TL, Wang Z, Liao Q, Zhu Y, Zhou WH, Xu W, Qiu Z

Abstract
Loss- and gain-of-function mutations of the X-linked gene MECP2 (methyl-CpG binding protein 2) lead to severe neurodevelopmental disorders in humans, such as Rett syndrome (RTT) and autism. MeCP2 is previously known as a transcriptional repressor by binding to methylated DNA and recruiting histone deacetylase complex (HDAC). Here, we report that MeCP2 regulates gene expression posttranscriptionally by suppressing nuclear microRNA processing. We found that MeCP2 binds directly to DiGeorge syndrome critical region 8 (DGCR8), a critical component of the nuclear microRNA-processing machinery, and interferes with the assembly of Drosha and DGCR8 complex. Protein targets of MeCP2-suppressed microRNAs include CREB, LIMK1, and Pumilio2, which play critical roles in neural development. Gain of function of MeCP2 strongly inhibits dendritic and spine growth, which depends on the interaction of MeCP2 and DGCR8. Thus, control of microRNA processing via direct interaction with DGCR8 represents a mechanism for MeCP2 regulation of gene expression and neural development.

PMID: 24636259 [PubMed - indexed for MEDLINE]

MeCP2 caught moonlighting as a suppressor of MicroRNA processing.

May 17, 2014 - 6:21am
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MeCP2 caught moonlighting as a suppressor of MicroRNA processing.

Dev Cell. 2014 Mar 10;28(5):477-8

Authors: Woo JS, Kim VN

Abstract
MeCP2 is a transcriptional regulator important for neurodevelopment and is involved in Rett syndrome and autism. In this issue of Developmental Cell, Cheng and colleagues (2014) report that MeCP2 also regulates microRNA biogenesis. MeCP2 phosphorylation induces a direct interaction with DGCR8, leading to reduced microRNA processing and retardation of dendritic growth.

PMID: 24636253 [PubMed - indexed for MEDLINE]

Interstitial 12p13.1 deletion involving GRIN2B in three patients with intellectual disability.

May 16, 2014 - 9:05am
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Interstitial 12p13.1 deletion involving GRIN2B in three patients with intellectual disability.

Am J Med Genet A. 2013 Oct;161(10):2564-9

Authors: Dimassi S, Andrieux J, Labalme A, Lesca G, Cordier MP, Boute O, Neut D, Edery P, Sanlaville D, Schluth-Bolard C

Abstract
We report on three patients presenting moderate intellectual disability, delayed language acquisition, and mild facial dysmorphia. Array-CGH studies revealed overlapping interstitial 12p13.1 microdeletions encompassing all or part of GRIN2B. GRIN2B encodes the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. This receptor is a heteromeric glutamate-activated ion channel, present throughout the central nervous system. It plays a critical role in corticogenesis, neuronal migration, and synaptogenesis during brain development. GRIN2B alterations, including mutation and gene disruption by apparently balanced chromosomal rearrangements, have been described in patients with intellectual disability and autism spectrum disorder. We report here on the first cases of GRIN2B deletion, enlarging the spectrum of GRIN2B abnormalities. Our findings confirm the involvement of this gene in neurodevelopmental disorders. © 2013 Wiley Periodicals, Inc.

PMID: 23918416 [PubMed - indexed for MEDLINE]

Sexual experience increases oxytocin receptor gene expression and protein in the medial preoptic area of the male rat.

May 16, 2014 - 9:05am
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Sexual experience increases oxytocin receptor gene expression and protein in the medial preoptic area of the male rat.

Psychoneuroendocrinology. 2013 Sep;38(9):1688-97

Authors: Gil M, Bhatt R, Picotte KB, Hull EM

Abstract
Oxytocin (OT) promotes social and reproductive behaviors in mammals, and OT deficits may be linked to disordered social behaviors like autism and severe anxiety. Male rat sexual behavior is an excellent model for OT regulation of behavior, as its pattern and neural substrates are well characterized. We previously reported that OT microinjected into the medial preoptic area (MPOA), a major integrative site for male sexual behavior, facilitates copulation in sexually experienced male rats, whereas intra-MPOA injection of an OT antagonist (OTA) inhibits copulation. In the present studies, copulation on the day of sacrifice stimulated OTR mRNA expression in the MPOA, irrespective of previous sexual experience, with the highest levels observed in first-time copulators. In addition, sexually experienced males had higher levels of OTR protein in the MPOA than sexually naïve males and first-time copulators. Finally, intra-MPOA injection of OT facilitated mating in sexually naive males. Others have reported a positive correlation between OT mRNA levels and male sexual behavior. Our studies show that OT in the MPOA facilitates mating in both sexually naive and experienced males, some of the behavioral effects of OT are mediated by the OTR, and sexual experience is associated with increased OTR expression in the MPOA. Taken together, these data suggest a reciprocal interaction between central OT and behavior, in which OT facilitates copulation and copulation stimulates the OT/OTR system in the brain.

PMID: 23474276 [PubMed - indexed for MEDLINE]

The frequency and risk factors of allergy and asthma in children with autism--case-control study.

May 10, 2014 - 7:15am
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The frequency and risk factors of allergy and asthma in children with autism--case-control study.

Przegl Epidemiol. 2013;67(4):675-9, 761-4

Authors: Mrozek-Budzyn D, Majewska R, Kiełyka A, Augustyniak M

Abstract
INTRODUCTION: The evolution of autistic disorders in children depends on many factors, like concomitance of the other diseases, which can escalate the autistic symptoms. One of those groups are allergic diseases, which have one of the highest prevalence rates in children.
OBJECTIVES: The aim of this analysis was to determine the frequency of asthma and allergy in children with autism in comparison to controls and the risk factors of allergic diseases and asthma in both groups.
MATERIAL AND METHODS: Study population included 96 cases diagnosed with childhood or atypical autism and 192 controls matched individually by year of birth, gender and physician's practice. The analysis was performed in each group separately giving possibility to compare the results between study groups.
RESULTS: The frequency of asthma and allergic diseases in both groups has not revealed any statistically significant differences. Children with autism have been affected by asthma in 5,2% and by allergy in 25,0%, controls in 4,7% and 21,9% respectively. All cases of asthma was diagnosed in boys, commonly allergy was also more frequent in boys than girls in both studied groups. However those differences was statistically insignificant. The father's allergy and asthma was revealed as a risk factor of allergy in children with autism. In controls additionally allergy or asthma diagnosed in mother or grandparent increased risk of allergy in children.
CONCLUSIONS: Children with autism were affected by asthma and allergy with similar frequency like children without autistic disorders. Allergy in father was the risk factor of allergic diseases in children with autism.

PMID: 24741916 [PubMed - indexed for MEDLINE]

Adult neuropsychiatric expression and familial segregation of 2q13 duplications.

May 9, 2014 - 4:10pm
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Adult neuropsychiatric expression and familial segregation of 2q13 duplications.

Am J Med Genet B Neuropsychiatr Genet. 2014 May 8;

Authors: Costain G, Lionel AC, Fu F, Stavropoulos DJ, Gazzellone MJ, Marshall CR, Scherer SW, Bassett AS

Abstract
New genomic disorders associated with large, rare, recurrent copy number variations (CNVs) are being discovered at a rapid pace. Detailed phenotyping and family studies are rare, however, as are data on adult phenotypic expression. Duplications at 2q13 were recently identified as risk factors for developmental delay/autism and reported in the prenatal setting, yet few individuals (all children) have been extensively phenotyped. During a genome-wide CNV study of schizophrenia, we identified two unrelated probands with 2q13 duplications. In this study, detailed phenotyping and genotyping using high-resolution microarrays was performed for 12 individuals across their two families. 2q13 duplications were present in six adults, and co-segregated with clinically significant later-onset neuropsychiatric disorders. Convergent lines of evidence implicated GABAminergic dysfunction. Analysis of the genic content revealed promising candidates for neuropsychiatric disease, including BCL2L11, ANAPC1, and MERTK. Intrafamilial genetic heterogeneity and "second hits" in one family may have been the consequence of assortative mating. Clinical genetic testing for the 2q13 duplication and the associated genetic counseling was well received. In summary, large rare 2q13 duplications appear to be associated with variable adult neuropsychiatric and other expression. The findings represent progress toward clinical translation of research results in schizophrenia. There are implications for other emerging genomic disorders where there is interest in lifelong expression. © 2014 Wiley Periodicals, Inc.

PMID: 24807792 [PubMed - as supplied by publisher]

Dolichol kinase deficiency (DOLK-CDG) with a purely neurological presentation caused by a novel mutation.

May 9, 2014 - 4:10pm
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Dolichol kinase deficiency (DOLK-CDG) with a purely neurological presentation caused by a novel mutation.

Mol Genet Metab. 2013 Nov;110(3):342-4

Authors: Helander A, Stödberg T, Jaeken J, Matthijs G, Eriksson M, Eggertsen G

Abstract
A 4-month old boy presented with multiple epileptic seizure types including West syndrome. Screening for infectious and structural etiologies showed normal results. A metabolic investigation was undertaken to investigate the cause of his neurological disease. Screening for congenital disorders of glycosylation (CDG) by HPLC analysis of serum carbohydrate-deficient transferrin (CDT) showed a type 1 pattern with 18% disialotransferrin (reference < 2%) and 2% asialotransferrin (reference 0). An undiagnosed 10-year old sister with a similar clinical history with infantile spasms at age 4 months, intellectual disability and an autism spectrum disorder, also showed a type 1 CDT pattern. Both siblings lacked dysmorphic features and extra-cerebral symptoms. The boy had cytotoxic edema of the thalamus and mesencephalon on MRI at age 7 months, whereas the girl had normal MRI at age 8 months. Phosphomannomutase (PMM) and phosphomannose isomerase (MPI) activities in cultured fibroblasts were normal, excluding PMM2-CDG and MPI-CDG. Fibroblast lipid-linked oligosaccharide analysis was also normal, suggesting an early defect in glycan assembly. Sequence analysis of the dolichol kinase gene revealed a homozygous new missense mutation (p.M1?; c.2 T > C) in both siblings. In conclusion, two siblings were demonstrated to suffer from DOLK-CDG (MIM 610768) and to be homozygous for a new mutation. They presented with West syndrome and so far show a purely neurological phenotype.

PMID: 23890587 [PubMed - indexed for MEDLINE]

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