pubmed: autism and genetics

Subscribe to pubmed: autism and genetics feed pubmed: autism and genetics
NCBI: db=pubmed; Term=autism AND genetics
Updated: 1 hour 21 min ago

Into, and out, of the "Valley of Death": research in autism spectrum disorders.

April 24, 2014 - 12:33pm
Related Articles

Into, and out, of the "Valley of Death": research in autism spectrum disorders.

J Am Acad Child Adolesc Psychiatry. 2012 Nov;51(11):1108-12

Authors: Szatmari P, Charman T, Constantino JN

PMID: 23101736 [PubMed - indexed for MEDLINE]

Neurotransmitter systems and neurotrophic factors in autism: association study of 37 genes suggests involvement of DDC.

April 24, 2014 - 12:33pm
Related Articles

Neurotransmitter systems and neurotrophic factors in autism: association study of 37 genes suggests involvement of DDC.

World J Biol Psychiatry. 2013 Sep;14(7):516-27

Authors: Toma C, Hervás A, Balmaña N, Salgado M, Maristany M, Vilella E, Aguilera F, Orejuela C, Cuscó I, Gallastegui F, Pérez-Jurado LA, Caballero-Andaluz R, Diego-Otero Yd, Guzmán-Alvarez G, Ramos-Quiroga JA, Ribasés M, Bayés M, Cormand B

Abstract
OBJECTIVES: Neurotransmitter systems and neurotrophic factors can be considered strong candidates for autism spectrum disorder (ASD). The serotoninergic and dopaminergic systems are involved in neurotransmission, brain maturation and cortical organization, while neurotrophic factors (NTFs) participate in neurodevelopment, neuronal survival and synapses formation. We aimed to test the contribution of these candidate pathways to autism through a case-control association study of genes selected both for their role in central nervous system functions and for pathophysiological evidences.
METHODS: The study sample consisted of 326 unrelated autistic patients and 350 gender-matched controls from Spain. We genotyped 369 tagSNPs to perform a case-control association study of 37 candidate genes.
RESULTS: A significant association was obtained between the DDC gene and autism in the single-marker analysis (rs6592961, P = 0.00047). Haplotype-based analysis pinpointed a four-marker combination in this gene associated with the disorder (rs2329340C-rs2044859T-rs6592961A-rs11761683T, P = 4.988e-05). No significant results were obtained for the remaining genes after applying multiple testing corrections. However, the rs167771 marker in DRD3, associated with ASD in a previous study, displayed a nominal association in our analysis (P = 0.023).
CONCLUSIONS: Our data suggest that common allelic variants in the DDC gene may be involved in autism susceptibility.

PMID: 22397633 [PubMed - indexed for MEDLINE]

Amniotic fluid inflammatory cytokines: potential markers of immunologic dysfunction in autism spectrum disorders.

April 24, 2014 - 12:33pm
Related Articles

Amniotic fluid inflammatory cytokines: potential markers of immunologic dysfunction in autism spectrum disorders.

World J Biol Psychiatry. 2013 Sep;14(7):528-38

Authors: Abdallah MW, Larsen N, Grove J, Nørgaard-Pedersen B, Thorsen P, Mortensen EL, Hougaard DM

Abstract
OBJECTIVES: The aim of the study was to analyze cytokine profiles in amniotic fluid (AF) samples of children developing autism spectrum disorders (ASD) and controls, adjusting for maternal autoimmune disorders and maternal infections during pregnancy.
METHODS: AF samples of 331 ASD cases and 698 controls were analyzed for inflammatory cytokines using Luminex xMAP technology utilizing a historic birth cohort. Clinical data were retrieved from nationwide registers, and case-control differences in AF cytokine levels were assessed using chi-square tests, logistic and tobit regression models.
RESULTS: Overall, individuals with ASD had significantly elevated AF levels of TNF-α and TNF-β compared to controls. Analyzing individuals diagnosed only with ICD-10 codes yielded significantly elevated levels of IL-4, IL-10, TNF-α and TNF-β in ASD patients. Restricting analysis to infantile autism cases showed significantly elevated levels of IL-4, TNF-α and TNF-β compared to controls with no psychiatric comorbidities. Elevated levels of IL-6 and IL-5 were found in individuals with other childhood psychiatric disorders (OCPD) when compared to controls with no psychiatric comorbidities.
CONCLUSIONS: AF samples of individuals with ASD or OCPD showed differential cytokine profiles compared to frequency-matched controls. Further studies to examine the specificity of the reported cytokine profiles in ASD and OCPD are required.

PMID: 22175527 [PubMed - indexed for MEDLINE]

The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment.

April 23, 2014 - 6:08am

The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment.

J Neural Transm. 2014 Apr 22;

Authors: Rojas DC

Abstract
Glutamate is the major excitatory neurotransmitter in the brain and may be a key neurotransmitter involved in autism. Literature pertaining to glutamate and autism or related disorders (e.g., Fragile X syndrome) is reviewed in this article. Interest in glutamatergic dysfunction in autism is high due to increasing convergent evidence implicating the system in the disorder from peripheral biomarkers, neuroimaging, protein expression, genetics and animal models. Currently, there are no pharmaceutical interventions approved for autism that address glutamate deficits in the disorder. New treatments related to glutamatergic neurotransmission, however, are emerging. In addition, older glutamate-modulating medications with approved indications for use in other disorders are being investigated for re-tasking as treatments for autism. This review presents evidence in support of glutamate abnormalities in autism and the potential for translation into new treatments for the disorder.

PMID: 24752754 [PubMed - as supplied by publisher]

The hippocampal CA2 region is essential for social memory.

April 23, 2014 - 6:08am
Related Articles

The hippocampal CA2 region is essential for social memory.

Nature. 2014 Apr 3;508(7494):88-92

Authors: Hitti FL, Siegelbaum SA

Abstract
The hippocampus is critical for encoding declarative memory, our repository of knowledge of who, what, where and when. Mnemonic information is processed in the hippocampus through several parallel routes involving distinct subregions. In the classic trisynaptic pathway, information proceeds from entorhinal cortex (EC) to dentate gyrus to CA3 and then to CA1, the main hippocampal output. Genetic lesions of EC (ref. 3) and hippocampal dentate gyrus (ref. 4), CA3 (ref. 5) and CA1 (ref. 6) regions have revealed their distinct functions in learning and memory. In contrast, little is known about the role of CA2, a relatively small area interposed between CA3 and CA1 that forms the nexus of a powerful disynaptic circuit linking EC input with CA1 output. Here we report a novel transgenic mouse line that enabled us to selectively examine the synaptic connections and behavioural role of the CA2 region in adult mice. Genetically targeted inactivation of CA2 pyramidal neurons caused a pronounced loss of social memory--the ability of an animal to remember a conspecific--with no change in sociability or several other hippocampus-dependent behaviours, including spatial and contextual memory. These behavioural and anatomical results thus reveal CA2 as a critical hub of sociocognitive memory processing.

PMID: 24572357 [PubMed - indexed for MEDLINE]

A de novo 2.3 Mb deletion in 2q24.2q24.3 in a 20-month-old developmentally delayed girl.

April 23, 2014 - 6:08am
Related Articles

A de novo 2.3 Mb deletion in 2q24.2q24.3 in a 20-month-old developmentally delayed girl.

Gene. 2014 Apr 10;539(1):168-72

Authors: Belengeanu V, Gamage TH, Farcas S, Stoian M, Andreescu N, Belengeanu A, Frengen E, Misceo D

Abstract
We report a 20-month-old girl ascertained at the age of 11 months for developmental delay. She presented with hypotonia and delayed motor development. The patient had severe language impairment and showed behaviour consistent with autism spectrum disorder. She was microcephalic with mild dysmorphic features and had joint hyperlaxity. We detected a 2.3 Mb de novo deletion in 2q24.2q24.3 on her paternal chromosome. We compare the clinical features of our patient to six previously published patients with a deletion in 2q24.2q24.3, and one patient reported in the ECARUCA database. Although the clinical presentation of these patients is not highly consistent, likely due to the different deletion size and gene content, the following features seem to be recurrent: disturbance in the central nervous system, poor growth, hypotonia, and joint hyperlaxity. The region deleted in our patient contains 13 genes including PSMD14, TBR1, SLC4A10, DPP4, KCNH7, and FIGN. We briefly review the knowledge of these genes and their possible involvement in the aetiology of this developmental delay syndrome.

PMID: 24508274 [PubMed - indexed for MEDLINE]

High-throughput sequencing of autism spectrum disorders comes of age.

April 23, 2014 - 6:08am
Related Articles

High-throughput sequencing of autism spectrum disorders comes of age.

Genet Res (Camb). 2013 Aug;95(4):121-9

Authors: Wang M, Fan X, Wang T, Wu J

Abstract
Autism spectrum disorders (ASDs) are lifelong neurodevelopmental disabilities that affect 1 in 88 children in the USA. Despite the high heritability, the genetic basis for a majority of the ASDs remains elusive. The considerable clinical and genetic heterogeneity pose a significant challenge technically. State-of-the-art high-throughput sequencing (HTS), which makes the analyses of any specific single/multiple genes or whole exomes feasible, has shown a promising perspective in disease gene discovery. To date, numerous genetic studies using HTS have been reported and many rare inherited or de novo mutations have been identified. This review will focus on the progress and prospective of genome studies of ASDs using HTS.

PMID: 24074369 [PubMed - indexed for MEDLINE]

Timing of mTOR activation affects tuberous sclerosis complex neuropathology in mouse models.

April 23, 2014 - 6:08am
Related Articles

Timing of mTOR activation affects tuberous sclerosis complex neuropathology in mouse models.

Dis Model Mech. 2013 Sep;6(5):1185-97

Authors: Magri L, Cominelli M, Cambiaghi M, Cursi M, Leocani L, Minicucci F, Poliani PL, Galli R

Abstract
Tuberous sclerosis complex (TSC) is a dominantly inherited disease with high penetrance and morbidity, and is caused by mutations in either of two genes, TSC1 or TSC2. Most affected individuals display severe neurological manifestations - such as intractable epilepsy, mental retardation and autism - that are intimately associated with peculiar CNS lesions known as cortical tubers (CTs). The existence of a significant genotype-phenotype correlation in individuals bearing mutations in either TSC1 or TSC2 is highly controversial. Similar to observations in humans, mouse modeling has suggested that a more severe phenotype is associated with mutation in Tsc2 rather than in Tsc1. However, in these mutant mice, deletion of either gene was achieved in differentiated astrocytes. Here, we report that loss of Tsc1 expression in undifferentiated radial glia cells (RGCs) early during development yields the same phenotype detected upon deletion of Tsc2 in the same cells. Indeed, the same aberrations in cortical cytoarchitecture, hippocampal disturbances and spontaneous epilepsy that have been detected in RGC-targeted Tsc2 mutants were observed in RGC-targeted Tsc1 mutant mice. Remarkably, thorough characterization of RGC-targeted Tsc1 mutants also highlighted subventricular zone (SVZ) disturbances as well as STAT3-dependent and -independent developmental-stage-specific defects in the differentiation potential of ex-vivo-derived embryonic and postnatal neural stem cells (NSCs). As such, deletion of either Tsc1 or Tsc2 induces mostly overlapping phenotypic neuropathological features when performed early during neurogenesis, thus suggesting that the timing of mTOR activation is a key event in proper neural development.

PMID: 23744272 [PubMed - indexed for MEDLINE]

Mining the 3'UTR of Autism-implicated Genes for SNPs Perturbing MicroRNA Regulation.

April 22, 2014 - 8:36am

Mining the 3'UTR of Autism-implicated Genes for SNPs Perturbing MicroRNA Regulation.

Genomics Proteomics Bioinformatics. 2014 Apr 16;

Authors: Vaishnavi V, Manikandan M, Munirajan AK

Abstract
Autism spectrum disorder (ASD) refers to a group of childhood neurodevelopmental disorders with polygenic etiology. The expression of many genes implicated in ASD is tightly regulated by various factors including microRNAs (miRNAs), a class of noncoding RNAs ∼22 nucleotides in length that function to suppress translation by pairing with 'miRNA recognition elements' (MREs) present in the 3'untranslated region (3'UTR) of target mRNAs. This emphasizes the role played by miRNAs in regulating neurogenesis, brain development and differentiation and hence any perturbations in this regulatory mechanism might affect these processes as well. Recently, single nucleotide polymorphisms (SNPs) present within 3'UTRs of mRNAs have been shown to modulate existing MREs or even create new MREs. Therefore, we hypothesized that SNPs perturbing miRNA-mediated gene regulation might lead to aberrant expression of autism-implicated genes, thus resulting in disease predisposition or pathogenesis in at least a subpopulation of ASD individuals. We developed a systematic computational pipeline that integrates data from well-established databases. By following a stringent selection criterion, we identified 9 MRE-modulating SNPs and another 12 MRE-creating SNPs in the 3'UTR of autism-implicated genes. These high-confidence candidate SNPs may play roles in ASD and hence would be valuable for further functional validation.

PMID: 24747189 [PubMed - as supplied by publisher]

De novo SCN2A splice site mutation in a boy with Autism spectrum disorder.

April 22, 2014 - 8:36am
Related Articles

De novo SCN2A splice site mutation in a boy with Autism spectrum disorder.

BMC Med Genet. 2014;15:35

Authors: Tavassoli T, Kolevzon A, Wang AT, Curchack-Lichtin J, Halpern D, Schwartz L, Soffes S, Bush L, Grodberg D, Cai G, Buxbaum JD

Abstract
BACKGROUND: SCN2A is a gene that codes for the alpha subunit of voltage-gated, type II sodium channels, and is highly expressed in the brain. Sodium channel disruptions, such as mutations in SCN2A, may play an important role in psychiatric disorders. Recently, de novo SCN2A mutations in autism spectrum disorder (ASD) have been identified. The current study characterizes a de novo splice site mutation in SCN2A that alters mRNA and protein products.
CASE PRESENTATION: We describe results from clinical and genetic characterizations of a seven-year-old boy with ASD. Psychiatric interview and gold standard autism diagnostic instruments (ADOS and ADI-R) were used to confirm ASD diagnosis, in addition to performing standardized cognitive and adaptive functioning assessments (Leiter-R and Vineland Adaptive Behavior Scale), and sensory reactivity assessments (Sensory Profile and Sensory Processing Scales). Genetic testing by whole exome sequencing revealed four de novo events, including a splice site mutation c.476 + 1G > A in SCN2A, a missense mutation (c.2263G > A) causing a p.V755I change in the TLE1 gene, and two synonymous mutations (c.2943A > G in the BUB1 gene, and c.1254 T > A in C10orf68 gene). The de novo SCN2A splice site mutation produced a stop codon 10 amino acids downstream, possibly resulting in a truncated protein and/or a nonsense-mediated mRNA decay. The participant met new DSM-5 criteria for ASD, presenting with social and communication impairment, repetitive behaviors, and sensory reactivity issues. The participant's adaptive and cognitive skills fell in the low range of functioning.
CONCLUSION: This report indicates that a splice site mutation in SCN2A might be contributing to the risk of ASD. Describing the specific phenotype associated with SCN2A mutations might help to reduce heterogeneity seen in ASD.

PMID: 24650168 [PubMed - indexed for MEDLINE]

Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening.

April 22, 2014 - 8:36am
Related Articles

Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening.

BMC Med Genet. 2014;15:26

Authors: Marchese M, Conti V, Valvo G, Moro F, Muratori F, Tancredi R, Santorelli FM, Guerrini R, Sicca F

Abstract
BACKGROUND: With a complex and extremely high clinical and genetic heterogeneity, autism spectrum disorders (ASD) are better dissected if one takes into account specific endophenotypes. Comorbidity of ASD with epilepsy (or paroxysmal EEG) has long been described and seems to have strong genetic background. Macrocephaly also represents a well-known endophenotype in subgroups of ASD individuals, which suggests pathogenic mechanisms accelerating brain growth in early development and predisposing to the disorder. We attempted to estimate the association of gene variants with neurodevelopmental disorders in patients with autism-epilepsy phenotype (AEP) and cranial overgrowth, analyzing two genes previously reported to be associated with autism and macrocephaly.
METHODS: We analyzed the coding sequences and exon-intron boundaries of GLIALCAM, encoding an IgG-like cell adhesion protein, in 81 individuals with Autism Spectrum Disorders, either with or without comorbid epilepsy, paroxysmal EEG and/or macrocephaly, and the PTEN gene in the subsample with macrocephaly.
RESULTS: Among 81 individuals with ASD, 31 had concurrent macrocephaly. Head circumference, moreover, was over the 99.7th percentile ("extreme" macrocephaly) in 6/31 (19%) patients. Whilst we detected in GLIALCAM several single nucleotide variants without clear pathogenic effects, we found a novel PTEN heterozygous frameshift mutation in one case with "extreme" macrocephaly, autism, intellectual disability and seizures.
CONCLUSIONS: We did not find a clear association between GLIALCAM mutations and AEP-macrocephaly comorbidity. The identification of a novel frameshift variant of PTEN in a patient with "extreme" macrocephaly, autism, intellectual disability and seizures, confirms this gene as a major candidate in the ASD-macrocephaly endophenotype. The concurrence of epilepsy in the same patient also suggests that PTEN, and the downstream signaling pathway, might deserve to be investigated in autism-epilepsy comorbidity. Working on clinical endophenotypes might be of help to address genetic studies and establish actual causative correlations in autism-epilepsy.

PMID: 24580998 [PubMed - indexed for MEDLINE]

Functional evaluation of autism-associated mutations in NHE9.

April 22, 2014 - 8:36am
Related Articles

Functional evaluation of autism-associated mutations in NHE9.

Nat Commun. 2013;4:2510

Authors: Kondapalli KC, Hack A, Schushan M, Landau M, Ben-Tal N, Rao R

Abstract
NHE9 (SLC9A9) is an endosomal cation/proton antiporter with orthologues in yeast and bacteria. Rare, missense substitutions in NHE9 are genetically linked with autism but have not been functionally evaluated. Here we use evolutionary conservation analysis to build a model structure of NHE9 based on the crystal structure of bacterial NhaA and use it to screen autism-associated variants in the human population first by phenotype complementation in yeast, followed by functional analysis in primary cortical astrocytes from mouse. NHE9-GFP localizes to recycling endosomes, where it significantly alkalinizes luminal pH, elevates uptake of transferrin and the neurotransmitter glutamate, and stabilizes surface expression of transferrin receptor and GLAST transporter. In contrast, autism-associated variants L236S, S438P and V176I lack function in astrocytes. Thus, we establish a neurobiological cell model of a candidate gene in autism. Loss-of-function mutations in NHE9 may contribute to autistic phenotype by modulating synaptic membrane protein expression and neurotransmitter clearance.

PMID: 24065030 [PubMed - indexed for MEDLINE]

Effects of age on male fertility.

April 22, 2014 - 8:36am
Related Articles

Effects of age on male fertility.

Best Pract Res Clin Endocrinol Metab. 2013 Aug;27(4):617-28

Authors: Zitzmann M

Abstract
Later parenting is considered by many to have advantages, parents-to-be may feel themselves more stable to rear children. In addition, many men start a second family later in life. Thus, paternal age becomes an emerging issue. Aging affects male fertility by a scope of factors, which are not fully understood to date. Generally, the amount of produced sperm cells as well as their motility decreases with age, as testicular histological architecture deteriorates. Decreased fecundity and an increased risk for disturbed pregnancies occur with advancing paternal age. Some rare autosomal dominant pathologies are clearly related to paternal age. Altered patterns of epigenetics/gene expression in aging sperm seem to affect a range of neurocognitive disorders and also metabolic dyshomeostasis across generations. Such effects refer to men older than 40 years and may have impact on socio-economic issues. Nevertheless, councelling of older men seeking paternity should be patient-oriented and weigh statistical probabilities against the right for individual life-planning.

PMID: 24054934 [PubMed - indexed for MEDLINE]

Translational approaches to the biology of Autism: false dawn or a new era?

April 22, 2014 - 8:36am
Related Articles

Translational approaches to the biology of Autism: false dawn or a new era?

Mol Psychiatry. 2013 Apr;18(4):435-42

Authors: Ecker C, Spooren W, Murphy DG

Abstract
Discovering novel treatments for Autism Spectrum Disorders (ASD) is a challenge. Its etiology and pathology remain largely unknown, the condition shows wide clinical diversity, and case identification is still solely based on symptomatology. Hence clinical trials typically include samples of biologically and clinically heterogeneous individuals. 'Core deficits', that is, deficits common to all individuals with ASD, are thus inherently difficult to find. Nevertheless, recent reports suggest that new opportunities are emerging, which may help develop new treatments and biomarkers for the condition. Most important, several risk gene variants have now been identified that significantly contribute to ASD susceptibility, many linked to synaptic functioning, excitation-inhibition balance, and brain connectivity. Second, neuroimaging studies have advanced our understanding of the 'wider' neural systems underlying ASD; and significantly contributed to our knowledge of the complex neurobiology associated with the condition. Last, the recent development of powerful multivariate analytical techniques now enable us to use multi-modal information in order to develop complex 'biomarker systems', which may in the future be used to assist the behavioral diagnosis, aid patient stratification and predict response to treatment/intervention. The aim of this review is, therefore, to summarize some of these important new findings and highlight their potential significant translational value to the future of ASD research.

PMID: 22801412 [PubMed - indexed for MEDLINE]

A neurodevelopmental perspective on the acquisition of nonverbal cognitive skills in adolescents with fragile X syndrome.

April 20, 2014 - 3:28pm
Related Articles

A neurodevelopmental perspective on the acquisition of nonverbal cognitive skills in adolescents with fragile X syndrome.

Dev Neuropsychol. 2013;38(7):445-60

Authors: Kover ST, Pierpont EI, Kim JS, Brown WT, Abbeduto L

Abstract
This longitudinal study was designed to investigate trajectories of nonverbal cognitive ability in adolescents with fragile X syndrome with respect to the relative influence of fragile X mental retardation protein (FMRP), autism symptom severity, and environmental factors on visualization and fluid reasoning abilities. Males and females with fragile X syndrome (N = 53; ages 10-16 years) were evaluated with the Leiter-R at up to four annual assessments. On average, IQ declined with age. FMRP levels predicted change in fluid reasoning, but not in visualization. The role of FMRP in the neural development that underlies the fragile X syndrome cognitive phenotype is discussed.

PMID: 24138215 [PubMed - indexed for MEDLINE]

The epigenetic switches for neural development and psychiatric disorders.

April 18, 2014 - 7:24am
Related Articles

The epigenetic switches for neural development and psychiatric disorders.

J Genet Genomics. 2013 Jul 20;40(7):339-46

Authors: Lv J, Xin Y, Zhou W, Qiu Z

Abstract
The most remarkable feature of the nervous system is that the development and functions of the brain are largely reshaped by postnatal experiences, in joint with genetic landscapes. The nature vs. nurture argument reminds us that both genetic and epigenetic information is indispensable for the normal function of the brain. The epigenetic regulatory mechanisms in the central nervous system have been revealed over last a decade. Moreover, the mutations of epigenetic modulator genes have been shown to be implicated in neuropsychiatric disorders, such as autism spectrum disorders. The epigenetic study has initiated in the neuroscience field for a relative short period of time. In this review, we will summarize recent discoveries about epigenetic regulation on neural development, synaptic plasticity, learning and memory, as well as neuropsychiatric disorders. Although the comprehensive view of how epigenetic regulation contributes to the function of the brain is still not completed, the notion that brain, the most complicated organ of organisms, is profoundly shaped by epigenetic switches is widely accepted.

PMID: 23876774 [PubMed - indexed for MEDLINE]

Maternally inherited genetic variants of CADPS2 are present in Autism Spectrum Disorders and Intellectual Disability patients.

April 17, 2014 - 6:17am

Maternally inherited genetic variants of CADPS2 are present in Autism Spectrum Disorders and Intellectual Disability patients.

EMBO Mol Med. 2014 Apr 14;

Authors: Bonora E, Graziano C, Minopoli F, Bacchelli E, Magini P, Diquigiovanni C, Lomartire S, Bianco F, Vargiolu M, Parchi P, Marasco E, Mantovani V, Rampoldi L, Trudu M, Parmeggiani A, Battaglia A, Mazzone L, Tortora G, IMGSAC, Maestrini E, Seri M, Romeo G

Abstract
Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients. We identified a novel intragenic deletion of maternal origin in two siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. CADPS2 allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue- and temporal-specific regulation in human and mice. We suggest that CADPS2 variants may contribute to ID/ASD development, possibly through a parent-of-origin effect.

PMID: 24737869 [PubMed - as supplied by publisher]

Hypermethylation of the enolase gene (ENO2) in autism.

April 17, 2014 - 6:17am

Hypermethylation of the enolase gene (ENO2) in autism.

Eur J Pediatr. 2014 Apr 17;

Authors: Wang Y, Fang Y, Zhang F, Xu M, Zhang J, Yan J, Ju W, Brown WT, Zhong N

Abstract
It has been hypothesized that dysregulation of brain-expressed genes is the major predisposing underlying mechanism for autism. This dysregulation may be mediated by differential methylation of CpG sites within gene promoters, which could be candidate biomarkers and used for early clinical screening of autism. A total of 131 pairs of age- and sex-matched autistic and control subjects were recruited in this study. Peripheral blood cells were analyzed. The first five pairs were randomly applied to array-based genome-wide methylation studies. A neuron-specific gene, ENO2, was found to be hypermethylated in the autistic samples. This difference was validated by bisulfite sequencing PCR (BSP). The differential expression of ENO2 gene was further analyzed with RT-qPCR and ELISA. The hypermethylation of ENO2 within the promoter region was confirmed by BSP to be present in 14.5 % (19/131) of the total of the autistic samples. The mean ENO2 RNA level in these 19 autistic samples was reduced by about 70 % relative to that in controls. The average level of ENO2 protein expression in the 19 autistic samples (15.18 ± 3.51 μg/l) was about half of that in the controls (33.86 ± 8.16 μg/l). Conclusion: These findings suggest that reduced ENO2 expression may be a biomarker for a subset of autistic children.

PMID: 24737292 [PubMed - as supplied by publisher]

Heat Shock Alters the Expression of Schizophrenia and Autism Candidate Genes in an Induced Pluripotent Stem Cell Model of the Human Telencephalon.

April 17, 2014 - 6:17am

Heat Shock Alters the Expression of Schizophrenia and Autism Candidate Genes in an Induced Pluripotent Stem Cell Model of the Human Telencephalon.

PLoS One. 2014;9(4):e94968

Authors: Lin M, Zhao D, Hrabovsky A, Pedrosa E, Zheng D, Lachman HM

Abstract
Schizophrenia (SZ) and autism spectrum disorders (ASD) are highly heritable neuropsychiatric disorders, although environmental factors, such as maternal immune activation (MIA), play a role as well. Cytokines mediate the effects of MIA on neurogenesis and behavior in animal models. However, MIA stimulators can also induce a febrile reaction, which could have independent effects on neurogenesis through heat shock (HS)-regulated cellular stress pathways. However, this has not been well-studied. To help understand the role of fever in MIA, we used a recently described model of human brain development in which induced pluripotent stem cells (iPSCs) differentiate into 3-dimensional neuronal aggregates that resemble a first trimester telencephalon. RNA-seq was carried out on aggregates that were heat shocked at 39°C for 24 hours, along with their control partners maintained at 37°C. 186 genes showed significant differences in expression following HS (p<0.05), including known HS-inducible genes, as expected, as well as those coding for NGFR and a number of SZ and ASD candidates, including SMARCA2, DPP10, ARNT2, AHI1 and ZNF804A. The degree to which the expression of these genes decrease or increase during HS is similar to that found in copy loss and copy gain copy number variants (CNVs), although the effects of HS are likely to be transient. The dramatic effect on the expression of some SZ and ASD genes places HS, and perhaps other cellular stressors, into a common conceptual framework with disease-causing genetic variants. The findings also suggest that some candidate genes that are assumed to have a relatively limited impact on SZ and ASD pathogenesis based on a small number of positive genetic findings, such as SMARCA2 and ARNT2, may in fact have a much more substantial role in these disorders - as targets of common environmental stressors.

PMID: 24736721 [PubMed - as supplied by publisher]

The Roots of Autism and ADHD Twin Study in Sweden (RATSS).

April 17, 2014 - 6:17am

The Roots of Autism and ADHD Twin Study in Sweden (RATSS).

Twin Res Hum Genet. 2014 Apr 15;:1-13

Authors: Bölte S, Willfors C, Berggren S, Norberg J, Poltrago L, Mevel K, Coco C, Fransson P, Borg J, Sitnikov R, Toro R, Tammimies K, Anderlid BM, Nordgren A, Falk A, Meyer U, Kere J, Landén M, Dalman C, Ronald A, Anckarsäter H, Lichtenstein P

Abstract
Neurodevelopmental disorders affect a substantial minority of the general population. Their origins are still largely unknown, but a complex interplay of genetic and environmental factors causing disturbances of the central nervous system's maturation and a variety of higher cognitive skills is presumed. Only limited research of rather small sample size and narrow scope has been conducted in neurodevelopmental disorders using a twin-differences design. The Roots of Autism and ADHD Twin Study in Sweden (RATSS) is an ongoing project targeting monozygotic twins discordant for categorical or dimensional autistic and inattentive/hyperactive-impulsive phenotypes as well as other neurodevelopmental disorders, and typically developing twin controls. Included pairs are 9 years of age or older, and comprehensively assessed for psychopathology, medical history, neuropsychology, and dysmorphology, as well as structural, functional, and molecular brain imaging. Specimens are collected for induced pluripotent (iPS) and neuroepithelial stem cells, genetic, gut bacteria, protein-/monoamine, and electron microscopy analyses. RATSS's objective is to generate a launch pad for novel surveys to understand the complexity of genotype-environment-phenotype interactions in autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD). By October 2013, RATSS had collected data from 55 twin pairs, among them 10 monozygotic pairs discordant for autism spectrum disorder, seven for ADHD, and four for other neurodevelopmental disorders. This article describes the design, recruitment, data collection, measures, collected pairs' characteristics, as well as ongoing and planned analyses in RATSS. Potential gains of the study comprise the identification of environmentally mediated biomarkers, the emergence of candidates for drug development, translational modeling, and new leads for prevention of incapacitating outcomes.

PMID: 24735654 [PubMed - as supplied by publisher]

Pages