pubmed: autism and genetics

Subscribe to pubmed: autism and genetics feed pubmed: autism and genetics
NCBI: db=pubmed; Term=autism AND genetics
Updated: 15 min 40 sec ago

Valproic acid downregulates Cdk5 activity via the transcription of the p35 mRNA.

August 15, 2014 - 7:43am
Related Articles

Valproic acid downregulates Cdk5 activity via the transcription of the p35 mRNA.

Biochem Biophys Res Commun. 2014 May 16;447(4):678-82

Authors: Takahashi M, Ishida M, Saito T, Ohshima T, Hisanaga S

Abstract
The cyclin-dependent kinase 5 (Cdk5) is a neuron-specific Ser/Thr kinase that is activated by the regulatory subunit p35. Overactivation of Cdk5, which is induced by the cleavage of p35 by calpain, is implicated in neuronal death in various neurodegenerative diseases. In contrast, depletion of the Cdk5 activity renders neurons vulnerable to stresses. Recent reports suggest the involvement of Cdk5 in mental disorders. We hypothesized that perturbation of Cdk5 activity is related to mental conditions. To verify this hypothesis, we investigated the effect of valproic acid (VPA), which is a drug of choice for psychiatric disorders, on Cdk5 activity. VPA decreased the expression of p35 at both the protein and mRNA levels in cultured neurons, resulting in a decrease of Cdk5 activity. VPA decreased the p35 mRNA via histone deacetylase inhibition. The chronic administration of VPA also downregulated p35 in mouse brains. These results indicate that VPA regulates Cdk5 activity in neurons via p35 transcription mediated by HDAC inhibition.

PMID: 24755075 [PubMed - indexed for MEDLINE]

Uncovering the etiology of autism spectrum disorders: genomics, bioinformatics, environment, data collection and exploration, and future possibilities.

August 15, 2014 - 7:43am
Related Articles

Uncovering the etiology of autism spectrum disorders: genomics, bioinformatics, environment, data collection and exploration, and future possibilities.

Pac Symp Biocomput. 2014;:422-6

Authors: Pendergrass S, Girirajan S, Selleck S

Abstract
A clear and predictive understanding of the etiology of autism spectrum disorders (ASD), a group of neurodevelopmental disorders characterized by varying deficits in social interaction and communication as well as repetitive behaviors, has not yet been achieved. There remains active debate about the origins of autism, and the degree to which genetic and environmental factors, and their interplay, produce the range and heterogeneity of cognitive, developmental, and behavioral features seen in children carrying a diagnosis of ASD. Unlocking the causes of these complex developmental disorders will require a collaboration of experts in many disciplines, including clinicians, environmental exposure experts, bioinformaticists, geneticists, and computer scientists. For this workshop we invited prominent researchers in the field of autism, covering a range of topics from genetic and environmental research to ethical considerations. The goal of this workshop: provide an introduction to the current state of autism research, highlighting the potential for multi-disciplinary collaborations that rigorously evaluate the many potential contributors to ASD. It is further anticipated that approaches that successfully advance the understanding of ASD can be applied to the study of other common, complex disorders. Herein we provide a short review of ASD and the work of the invited speakers.

PMID: 24297568 [PubMed - indexed for MEDLINE]

The glial perspective of autism spectrum disorders.

August 13, 2014 - 6:43am
Related Articles

The glial perspective of autism spectrum disorders.

Neurosci Biobehav Rev. 2014 Jan;38:160-72

Authors: Zeidán-Chuliá F, Salmina AB, Malinovskaya NA, Noda M, Verkhratsky A, Moreira JC

Abstract
The aetiology of autism spectrum disorders remains unclear although a growing number of associated genetic abnormalities and environmental factors have been discovered in recent decades. These advancements coincided with a remarkable increase in the comprehension of physiological functions and pathological potential of neuroglia in the central nervous system that led to a notion of fundamental contribution of glial cells into multiple neuropathologies, including neuropsychiatric and developmental disorders. Growing evidence indicates a role for deregulation of astroglial control over homeostasis and plastic potential of neural networks as well as microglial malfunction and neuroinflammatory response in the brains of autistic patients. In this review, we shall summarize the status and pathological potential of neuroglia and argue for neuroglial roots of autistic disorders.

PMID: 24300694 [PubMed - in process]

Parental influence on a child's autistic traits.

August 13, 2014 - 6:43am
Related Articles

Parental influence on a child's autistic traits.

J Dev Behav Pediatr. 2013 Nov-Dec;34(9):730-2

Authors: Phelps R, Nickel R, Eisert D, Stein MT

Abstract
CASE: Robbie is a 4-year-old boy whose parents are concerned about his speech, social skills, and repetitive behaviors. He has poor articulation; at time, he is difficult to understand. On the other hand, he has a fair vocabulary, and he has good intent to communicate. He is generally able to communicate his needs and wants. He likes to tell his parents about his day. When he begins the day at preschool, Robbie initially stands by himself and watches. He slowly warms up and eventually participates in activities. He engages in parallel play or follows other children. He knows names of children at preschool, and he is well liked. He is affectionate with his parents. When Robbie is excited, he wiggles his fingers, flaps his arms, and grimaces. He can be quite rigid; for example, he gets very distressed when his mother sets his cup down on his right side instead of his left. However, in general, Robbie has a sunny personality. He likes to watch children's television shows. He pretends plays with action figures. Robbie is an only child who lives with both parents. His mother works full-time, and his father is in home with Robbie during the day. When examined in the office, Robbie had a bright affect, good eye contact, and social referencing. He demonstrated good communicative intent, but poor articulation and some jargoning. He frequently wiggled his fingers and flapped his hands with excitement. Robbie had a borderline score on the Autism Diagnostic Observation Schedule. During the visit, the pediatrician noted that Robbie's father was rather quiet and rarely responded to questions. When he did respond, he had a monotone quality to his voice. He maintained either a flat or nervous affect throughout the visit. He made limited eye contact, and occasionally he stared excessively.

PMID: 24217028 [PubMed - in process]

Different neurodevelopmental symptoms have a common genetic etiology.

August 13, 2014 - 6:43am
Related Articles

Different neurodevelopmental symptoms have a common genetic etiology.

J Child Psychol Psychiatry. 2013 Dec;54(12):1356-65

Authors: Pettersson E, Anckarsäter H, Gillberg C, Lichtenstein P

Abstract
BACKGROUND: Although neurodevelopmental disorders are demarcated as discrete entities in the Diagnostic Statistical Manual of mental disorders, empirical evidence indicates that there is a high degree of overlap among them. The first aim of this investigation was to explore if a single general factor could account for the large degree of observed overlap among neurodevelopmental problems, and explore whether this potential factor was primarily genetic or environmental in origin. The second aim was to explore whether there was systematic covariation, either genetic or environmental, over and above that contributed by the potential general factor, unique to each syndrome.
METHOD: Parents of all Swedish 9- and 12-year-old twin pairs born between 1992 and 2002 were targeted for interview regarding problems typical of autism spectrum disorders, ADHD and other neurodevelopmental conditions (response rate: 80 percent). Structural equation modeling was conducted on 6,595 pairs to examine the genetic and environmental structure of 53 neurodevelopmental problems.
RESULTS: One general genetic factor accounted for a large proportion of the phenotypic covariation among the 53 symptoms. Three specific genetic subfactors identified 'impulsivity,' 'learning problems,' and 'tics and autism,' respectively. Three unique environment factors identified 'autism,' 'hyperactivity and impulsivity,' and 'inattention and learning problems,' respectively.
CONCLUSION: One general genetic factor was responsible for the wide-spread phenotypic overlap among all neurodevelopmental symptoms, highlighting the importance of addressing broad patient needs rather than specific diagnoses. The unique genetic factors may help guide diagnostic nomenclature, whereas the unique environmental factors may highlight that neurodevelopmental symptoms are responsive to change at the individual level and may provide clues into different mechanisms and treatments. Future research would benefit from assessing the general factor separately from specific factors to better understand observed overlap among neurodevelopmental problems.

PMID: 24127638 [PubMed - in process]

Autism traits in the RASopathies.

August 13, 2014 - 6:43am
Related Articles

Autism traits in the RASopathies.

J Med Genet. 2014 Jan;51(1):10-20

Authors: Adviento B, Corbin IL, Widjaja F, Desachy G, Enrique N, Rosser T, Risi S, Marco EJ, Hendren RL, Bearden CE, Rauen KA, Weiss LA

Abstract
BACKGROUND: Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs.
METHODS: We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS).
RESULTS: Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs.
CONCLUSIONS: Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.

PMID: 24101678 [PubMed - in process]

Candidate gene associations with withdrawn behavior.

August 13, 2014 - 6:43am
Related Articles

Candidate gene associations with withdrawn behavior.

J Child Psychol Psychiatry. 2013 Dec;54(12):1337-45

Authors: Rubin DH, Althoff RR, Ehli EA, Davies GE, Rettew DC, Crehan ET, Walkup JT, Hudziak JJ

Abstract
BACKGROUND: Social withdrawal is a core neuropsychiatric phenomenon in developmental psychopathology. Its presence predicts psychopathology across many domains, including depression, psychosis, autism, anxiety, and suicide. Withdrawn behavior is highly heritable, persistent, and characteristically worsens without intervention. To date, few studies have successfully identified genetic associations with withdrawn behavior, despite the abundance of evidence of its heritability. This may be due to reliance of categorical over dimensional measures of the behaviorally inhibited phenotype. The aim of this study is to identify associations between known psychiatric candidate genes and a dimensionally derived measure of withdrawn behavior.
METHODS: Genetic information was collected on 20 single-nucleotide polymorphisms (SNPs) from a custom-designed SNP chip and TAQMAN arrays of 4 variable number of tandem repeat (VNTR) genes for 551 individuals from 187 families. Linear mixed modeling was employed to examine the relationship between genotypes of interest and Child Behavior Checklist (CBCL) Withdrawn Behavior Subscale Score (WBS) while controlling for gender and age through multiple linear regressions.
RESULTS: Withdrawn behavior was highly associated with polymorphism rs6314 of the serotonin receptor 2A (HTR2A) [p = .009, estimate = 0.310 (bootstrap 95% CI 0.155-0.448), bootstrap p = .001] and rs1800544 of the alpha 2-adrenergic (ADRA2A) [p = .001, estimate = -0.310 (bootstrap 95% CI -0.479 to -0.126), bootstrap p = .001] genes after correction for gender and age. The association between withdrawn behavior and ADRA2A was stronger for younger children.
CONCLUSIONS: HTR2A and ADRA2A genes are associated with withdrawn behavior. This reinforces the role of catecholaminergic genes in the heritability of withdrawn behavior.

PMID: 23808549 [PubMed - in process]

Shank mutant mice as an animal model of autism.

August 12, 2014 - 8:46am
Related Articles

Shank mutant mice as an animal model of autism.

Philos Trans R Soc Lond B Biol Sci. 2014 Jan 5;369(1633):20130143

Authors: Yoo J, Bakes J, Bradley C, Collingridge GL, Kaang BK

Abstract
In this review, we focus on the role of the Shank family of proteins in autism. In recent years, autism research has been flourishing. With genetic, molecular, imaging and electrophysiological studies being supported by behavioural studies using animal models, there is real hope that we may soon understand the fundamental pathology of autism. There is also genuine potential to develop a molecular-level pharmacological treatment that may be able to deal with the most severe symptoms of autism, and clinical trials are already underway. The Shank family of proteins has been strongly implicated as a contributing factor in autism in certain individuals and sits at the core of the alleged autistic pathway. Here, we analyse studies that relate Shank to autism and discuss what light this sheds on the possible causes of autism.

PMID: 24298145 [PubMed - indexed for MEDLINE]

Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice.

August 12, 2014 - 8:46am
Related Articles

Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice.

Biol Psychiatry. 2014 Feb 1;75(3):198-206

Authors: Franklin AV, King MK, Palomo V, Martinez A, McMahon LL, Jope RS

Abstract
BACKGROUND: Identifying feasible therapeutic interventions is crucial for ameliorating the intellectual disability and other afflictions of fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism. Hippocampal glycogen synthase kinase-3 (GSK3) is hyperactive in the mouse model of FXS (FX mice), and hyperactive GSK3 promotes locomotor hyperactivity and audiogenic seizure susceptibility in FX mice, raising the possibility that specific GSK3 inhibitors may improve cognitive processes.
METHODS: We tested if specific GSK3 inhibitors improve deficits in N-methyl-D-aspartate receptor-dependent long-term potentiation at medial perforant path synapses onto dentate granule cells and dentate gyrus-dependent cognitive behavioral tasks.
RESULTS: GSK3 inhibitors completely rescued deficits in long-term potentiation at medial perforant path-dentate granule cells synapses in FX mice. Furthermore, synaptosomes from the dentate gyrus of FX mice displayed decreased inhibitory serine-phosphorylation of GSK3β compared with wild-type littermates. The potential therapeutic utility of GSK3 inhibitors was further tested on dentate gyrus-dependent cognitive behaviors. In vivo administration of GSK3 inhibitors completely reversed impairments in several cognitive tasks in FX mice, including novel object detection, coordinate and categorical spatial processing, and temporal ordering for visual objects.
CONCLUSIONS: These findings establish that synaptic plasticity and cognitive deficits in FX mice can be improved by intervention with inhibitors of GSK3, which may prove therapeutically beneficial in FXS.

PMID: 24041505 [PubMed - indexed for MEDLINE]

A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation.

August 8, 2014 - 6:11am

A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation.

J Hum Genet. 2014 Aug 7;

Authors: Saitsu H, Tohyama J, Walsh T, Kato M, Kobayashi Y, Lee M, Tsurusaki Y, Miyake N, Goto YI, Nishino I, Ohtake A, King MC, Matsumoto N

Abstract
Recently, de novo mutations in TBL1XR1 were found in two patients with autism spectrum disorders. Here, we report on a Japanese girl presenting with West syndrome, Rett syndrome-like and autistic features. Her initial development was normal until she developed a series of spasms at 5 months of age. Electroencephalogram at 7 months showed a pattern of hypsarrhythmia, which led to a diagnosis of West syndrome. Stereotypic hand movements appeared at 8 months of age, and autistic features such as deficits in communication, hyperactivity and excitability were observed later, at 4 years and 9 months. Whole exome sequencing of the patient and her parents revealed a de novo TBL1XR1 mutation [c.209 G>A (p.Gly70Asp)] occurring at an evolutionarily conserved amino acid in an F-box-like domain. Our report expands the clinical spectrum of TBL1XR1 mutations to West syndrome with Rett-like features, together with autistic features.Journal of Human Genetics advance online publication, 7 August 2014; doi:10.1038/jhg.2014.71.

PMID: 25102098 [PubMed - as supplied by publisher]

Role of Metabolic Genes in Blood Arsenic Concentrations of Jamaican Children with and without Autism Spectrum Disorder.

August 8, 2014 - 6:11am

Role of Metabolic Genes in Blood Arsenic Concentrations of Jamaican Children with and without Autism Spectrum Disorder.

Int J Environ Res Public Health. 2014;11(8):7874-7895

Authors: Rahbar MH, Samms-Vaughan M, Ma J, Bressler J, Loveland KA, Ardjomand-Hessabi M, Dickerson AS, Grove ML, Shakespeare-Pellington S, Beecher C, McLaughlin W, Boerwinkle E

Abstract
Arsenic is a toxic metalloid with known adverse effects on human health. Glutathione-S-transferase (GST) genes, including GSTT1, GSTP1, and GSTM1, play a major role in detoxification and metabolism of xenobiotics. We investigated the association between GST genotypes and whole blood arsenic concentrations (BASC) in Jamaican children with and without autism spectrum disorder (ASD). We used data from 100 ASD cases and their 1:1 age- and sex-matched typically developing (TD) controls (age 2-8 years) from Jamaica. Using log-transformed BASC as the dependent variable in a General Linear Model, we observed a significant interaction between GSTP1 and ASD case status while controlling for several confounding variables. However, for GSTT1 and GSTM1 we did not observe any significant associations with BASC. Our findings indicate that TD children who had the Ile/Ile or Ile/Val genotype for GSTP1 had a significantly higher geometric mean BASC than those with genotype Val/Val (3.67 µg/L vs. 2.69 µg/L, p < 0.01). Although, among the ASD cases, this difference was not statistically significant, the direction of the observed difference was consistent with that of the TD control children. These findings suggest a possible role of GSTP1 in the detoxification of arsenic.

PMID: 25101770 [PubMed - as supplied by publisher]

Dysregulated nitric oxide signaling as a candidate mechanism of fragile X syndrome and other neuropsychiatric disorders.

August 8, 2014 - 6:11am

Dysregulated nitric oxide signaling as a candidate mechanism of fragile X syndrome and other neuropsychiatric disorders.

Front Genet. 2014;5:239

Authors: Colvin SM, Kwan KY

Abstract
A mechanistic understanding of the pathophysiology underpinning psychiatric disorders is essential for the development of targeted molecular therapies. For fragile X syndrome (FXS), recent mechanistic studies have been focused on the metabotropic glutamate receptor (mGluR) signaling pathway. This line of research has led to the discovery of promising candidate drugs currently undergoing various phases of clinical trial, and represents a model of how biological insights can inform therapeutic strategies in neurodevelopmental disorders. Although mGluR signaling is a key mechanism at which targeted treatments can be directed, it is likely to be one of many mechanisms contributing to FXS. A more complete understanding of the molecular and neural underpinnings of the disorder is expected to inform additional therapeutic strategies. Alterations in the assembly of neural circuits in the neocortex have been recently implicated in genetic studies of autism and schizophrenia, and may also contribute to FXS. In this review, we explore dysregulated nitric oxide signaling in the developing neocortex as a novel candidate mechanism of FXS. This possibility stems from our previous work demonstrating that neuronal nitric oxide synthase 1 (NOS1 or nNOS) is regulated by the FXS protein FMRP in the mid-fetal human neocortex. Remarkably, in the mid-late fetal and early postnatal neocortex of human FXS patients, NOS1 expression is severely diminished. Given the role of nitric oxide in diverse neural processes, including synaptic development and plasticity, the loss of NOS1 in FXS may contribute to the etiology of the disorder. Here, we outline the genetic and neurobiological data that implicate neocortical dysfunction in FXS, review the evidence supporting dysregulated nitric oxide signaling in the developing FXS neocortex and its contribution to the disorder, and discuss the implications for targeting nitric oxide signaling in the treatment of FXS and other psychiatric illnesses.

PMID: 25101118 [PubMed]

Bias towards large genes in autism.

August 8, 2014 - 6:11am

Bias towards large genes in autism.

Nature. 2014 Aug 7;512(7512):E1-2

Authors: Shohat S, Shifman S

PMID: 25100484 [PubMed - in process]

BDNF in fragile X syndrome.

August 7, 2014 - 8:32am
Related Articles

BDNF in fragile X syndrome.

Neuropharmacology. 2014 Jan;76 Pt C:729-36

Authors: Castrén ML, Castrén E

Abstract
Fragile X syndrome (FXS) is a monogenic disorder that is caused by the absence of FMR1 protein (FMRP). FXS serves as an excellent model disorder for studies investigating disturbed molecular mechanisms and synapse function underlying cognitive impairment, autism, and behavioral disturbance. Abnormalities in dendritic spines and synaptic transmission in the brain of FXS individuals and mouse models for FXS indicate perturbations in the development, maintenance, and plasticity of neuronal network connectivity. However, numerous alterations are found during the early development in FXS, including abnormal differentiation of neural progenitors and impaired migration of newly born neurons. Several aspects of FMRP function are modulated by brain-derived neurotrophic factor (BDNF) signaling. Here, we review the evidence of the role for BDNF in the developing and adult FXS brain. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

PMID: 23727436 [PubMed - indexed for MEDLINE]

Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression.

August 6, 2014 - 7:35am

Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression.

Mol Psychiatry. 2014 Aug 5;

Authors: Milekic MH, Xin Y, O'Donnell A, Kumar KK, Bradley-Moore M, Malaspina D, Moore H, Brunner D, Ge Y, Edwards J, Paul S, Haghighi FG, Gingrich JA

Abstract
Advanced paternal age (APA) has been shown to be a significant risk factor in the offspring for neurodevelopmental psychiatric disorders, such as schizophrenia and autism spectrum disorders. During aging, de novo mutations accumulate in the male germline and are frequently transmitted to the offspring with deleterious effects. In addition, DNA methylation during spermatogenesis is an active process, which is susceptible to errors that can be propagated to subsequent generations. Here we test the hypothesis that the integrity of germline DNA methylation is compromised during the aging process. A genome-wide DNA methylation screen comparing sperm from young and old mice revealed a significant loss of methylation in the older mice in regions associated with transcriptional regulation. The offspring of older fathers had reduced exploratory and startle behaviors and exhibited similar brain DNA methylation abnormalities as observed in the paternal sperm. Offspring from old fathers also had transcriptional dysregulation of developmental genes implicated in autism and schizophrenia. Our findings demonstrate that DNA methylation abnormalities arising in the sperm of old fathers are a plausible mechanism to explain some of the risks that APA poses to resulting offspring.Molecular Psychiatry advance online publication, 5 August 2014; doi:10.1038/mp.2014.84.

PMID: 25092244 [PubMed - as supplied by publisher]

Pages