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STRIPAK complexes: structure, biological function, and involvement in human diseases.

November 7, 2014 - 7:26am
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STRIPAK complexes: structure, biological function, and involvement in human diseases.

Int J Biochem Cell Biol. 2014 Feb;47:118-48

Authors: Hwang J, Pallas DC

Abstract
The mammalian striatin family consists of three proteins, striatin, S/G2 nuclear autoantigen, and zinedin. Striatin family members have no intrinsic catalytic activity, but rather function as scaffolding proteins. Remarkably, they organize multiple diverse, large signaling complexes that participate in a variety of cellular processes. Moreover, they appear to be regulatory/targeting subunits for the major eukaryotic serine/threonine protein phosphatase 2A. In addition, striatin family members associate with germinal center kinase III kinases as well as other novel components, earning these assemblies the name striatin-interacting phosphatase and kinase (STRIPAK) complexes. Recently, there has been a great increase in functional and mechanistic studies aimed at identifying and understanding the roles of STRIPAK and STRIPAK-like complexes in cellular processes of multiple organisms. These studies have identified novel STRIPAK and STRIPAK-like complexes and have explored their roles in specific signaling pathways. Together, the results of these studies have sparked increased interest in striatin family complexes because they have revealed roles in signaling, cell cycle control, apoptosis, vesicular trafficking, Golgi assembly, cell polarity, cell migration, neural and vascular development, and cardiac function. Moreover, STRIPAK complexes have been connected to clinical conditions, including cardiac disease, diabetes, autism, and cerebral cavernous malformation. In this review, we discuss the expression, localization, and protein domain structure of striatin family members. Then we consider the diverse complexes these proteins and their homologs form in various organisms, emphasizing what is known regarding function and regulation. Finally, we explore possible roles of striatin family complexes in disease, especially cerebral cavernous malformation.

PMID: 24333164 [PubMed - indexed for MEDLINE]

No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia.

November 6, 2014 - 7:13am

No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia.

Eur J Hum Genet. 2014 Nov 5;

Authors: Ruderfer DM, Lim ET, Genovese G, Moran JL, Hultman CM, Sullivan PF, McCarroll SA, Holmans P, Sklar P, Purcell SM

Abstract
Recessive inheritance of gene disrupting alleles, either through homozygosity at a specific site or compound heterozygosity, have been demonstrated to underlie many Mendelian diseases and some complex psychiatric disorders. On the basis of exome sequencing data, an increased burden of complete knockout (homozygous or compound heterozygous) variants has been identified in autism. In addition, using single-nucleotide polymorphism microarray data, an increased rate of homozygosity by descent, or autozygosity, has been linked to the risk of schizophrenia (SCZ). Here, in a large Swedish case-control SCZ sample (11 244 individuals, 5079 of whom have exome sequence data available), we survey the contribution of both autozygosity and complete knockouts to disease risk. We do not find evidence for association with SCZ, either genome wide or at specific loci. However, we note the possible impact of sample size and population genetic factors on the power to detect and quantify any burden that may exist.European Journal of Human Genetics advance online publication, 5 November 2014; doi:10.1038/ejhg.2014.228.

PMID: 25370044 [PubMed - as supplied by publisher]

Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy.

November 5, 2014 - 7:08am
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Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy.

Am J Med Genet A. 2014 Mar;164A(3):782-8

Authors: Kamien B, Harraway J, Lundie B, Smallhorne L, Gibbs V, Heath A, Fullerton JM

Abstract
We present a patient with a behavioral disorder, epilepsy, and autism spectrum disorder who has a 520 kb chromosomal deletion at 15q26.1 encompassing three genes: ST8SIA2, C15orf32, and FAM174B. Alpha-2,8-Sialyltransferase 2 (ST8SIA2) is expressed in the developing brain and appears to play an important role in neuronal migration, axon guidance and synaptic plasticity. It has recently been implicated in a genome wide association study as a potential factor underlying autism, and has also been implicated in the pathogenesis of bipolar disorder and schizophrenia. This case provides supportive evidence that ST8SIA2 haploinsufficiency may play a role in neurobehavioral phenotypes.

PMID: 24357335 [PubMed - indexed for MEDLINE]

Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome down to 1.6 Mb including PAX6, WT1, and PRRG4.

November 5, 2014 - 7:08am
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Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome down to 1.6 Mb including PAX6, WT1, and PRRG4.

Am J Med Genet A. 2014 Mar;164A(3):634-8

Authors: Yamamoto T, Togawa M, Shimada S, Sangu N, Shimojima K, Okamoto N

Abstract
Interstitial deletions of the 11p13 region are known to cause WAGR (Wilms tumor, aniridia, genitourinary malformation, and "mental retardation") syndrome, a contiguous gene deletion syndrome due to haploinsufficiencies of the genes in this region, including WT1 and PAX6. Developmental delay and autistic features are major complications of this syndrome. Previously, some genes located in this region have been suggested as responsible for autistic features. In this study, we identified two patients who showed the chromosomal deletions involving 11p13. Patient 1, having an 8.6 Mb deletion of chr11p14.1p12:29,676,434-38,237,948, exhibited a phenotype typical of WAGR syndrome and had severe developmental delay and autistic behaviors. On the other hand, Patient 2 had a larger aberration region in 11p14.1-p12 which was split into two regions, that is, a 2.2-Mb region of chr11p14.1: 29,195,161-31,349,732 and a 10.5-Mb region of chr11p13p12: 32,990,627-43,492,580. As a consequence, 1.6 Mb region of the WAGR syndrome critical region was intact between the two deletions. This patient showed no symptom of WAGR syndrome and no autistic behaviors. Therefore, the region responsible for severe developmental delay and autistic features on WAGR syndrome can be narrowed down to the region remaining intact in Patient 2. Thus, the unique genotype identified in this study suggested that haploinsufficiencies of PAX6 or PRRG4 included in this region are candidate genes for severe developmental delay and autistic features characteristic of WAGR syndrome.

PMID: 24357251 [PubMed - indexed for MEDLINE]

Sarm1, a neuronal inflammatory regulator, controls social interaction, associative memory and cognitive flexibility in mice.

November 5, 2014 - 7:08am
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Sarm1, a neuronal inflammatory regulator, controls social interaction, associative memory and cognitive flexibility in mice.

Brain Behav Immun. 2014 Mar;37:142-51

Authors: Lin CW, Hsueh YP

Abstract
Impaired neurodevelopment leads to several psychiatric disorders, including autism, schizophrenia and attention deficiency hyperactivity disorder. Our prior study showed that sterile alpha and TIR motif-containing 1 protein (Sarm1) regulates neuronal morphogenesis through at least two pathways. Sarm1 controls neuronal morphogenesis, including dendritic arborization, axonal outgrowth and establishment of neuronal polarity, through the MKK-JNK pathway. Neuronally expressed Sarm1 also regulates the expression of inflammatory cytokines in the brain, which have also been shown to impact brain development and function. Because the reduction of Sarm1 expression negatively influences neuronal development, here we investigated whether Sarm1 controls mouse behaviors. We analyzed two independent Sarm1 transgenic mouse lines using a series of behavioral assays, and found that the reduction of Sarm1 protein levels had a limited effect on locomotion and anxiety. However, Sarm1 knockdown mice exhibited impairments in cued and contextual fear conditioning as well as cognitive flexibility. Moreover, the three-chambered social test, reciprocal social interaction and social transmission of food preference further illustrated deficiencies in Sarm1 knockdown mice in social interaction. These findings suggest that Sarm1, a molecule that regulates innate immunity and neuronal morphogenesis, regulates social behaviors and cognition. We conclude that Sarm1 is involved in immune response, neural development and psychiatric disorders.

PMID: 24321214 [PubMed - indexed for MEDLINE]

Epilepsy associated with autism and attention deficit hyperactivity disorder: is there a genetic link?

November 5, 2014 - 7:08am
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Epilepsy associated with autism and attention deficit hyperactivity disorder: is there a genetic link?

Brain Dev. 2014 Mar;36(3):185-93

Authors: Lo-Castro A, Curatolo P

Abstract
Autism Spectrum Disorders (ASDs) and Attention Deficit and Hyperactivity Disorder (ADHD) are the most common comorbid conditions associated with childhood epilepsy. The co-occurrence of an epilepsy/autism phenotype or an epilepsy/ADHD phenotype has a complex and heterogeneous pathogenesis, resulting from several altered neurobiological mechanisms involved in early brain development, and influencing synaptic plasticity, neurotransmission and functional connectivity. Rare clinically relevant chromosomal aberrations, in addition to environmental factors, may confer an increased risk for ASDs/ADHD comorbid with epilepsy. The majority of the candidate genes are involved in synaptic formation/remodeling/maintenance (NRX1, CNTN4, DCLK2, CNTNAP2, TRIM32, ASTN2, CTNTN5, SYN1), neurotransmission (SYNGAP1, GABRG1, CHRNA7), or DNA methylation/chromatin remodeling (MBD5). Two genetic disorders, such as Tuberous sclerosis and Fragile X syndrome may serve as models for understanding the common pathogenic pathways leading to ASDs and ADHD comorbidities in children with epilepsy, offering the potential for new biologically focused treatment options.

PMID: 23726375 [PubMed - indexed for MEDLINE]

Stem cells and modeling of autism spectrum disorders.

November 5, 2014 - 7:08am
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Stem cells and modeling of autism spectrum disorders.

Exp Neurol. 2014 Oct;260:33-43

Authors: Freitas BC, Trujillo CA, Carromeu C, Yusupova M, Herai RH, Muotri AR

Abstract
Human neurons, generated from reprogrammed somatic cells isolated from live patients, bring a new perspective on the understanding of Autism Spectrum Disorders (ASD). The new technology can nicely complement other models for basic research and the development of therapeutic compounds aiming to revert or ameliorate the condition. Here, we discuss recent advances on the use of stem cells and other models to study ASDs, as well as their limitations, implications and future perspectives.

PMID: 23036599 [PubMed - indexed for MEDLINE]

MACROD2 gene associated with autistic-like traits in a general population sample.

November 2, 2014 - 6:06am
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MACROD2 gene associated with autistic-like traits in a general population sample.

Psychiatr Genet. 2014 Dec;24(6):241-248

Authors: Jones RM, Cadby G, Blangero J, Abraham LJ, Whitehouse AJ, Moses EK

Abstract
There is now substantial evidence that autistic-like traits in the general population lie on a continuum, with clinical autism spectrum disorders (ASD) representing the extreme end of this distribution. In this study, we sought to evaluate five independently identified genetic associations with ASD with autistic-like traits in the general population. In the study cohort, clinical phenotype and genomewide association genotype data were obtained from the Western Australian Pregnancy Cohort (Raine) Study. The outcome measure used was the Autism Spectrum Quotient (AQ), a quantitative measure of autistic-like traits of individuals in the cohort. Total AQ scores were calculated for each individual, as well as scores for three subscales. Five candidate single nucleotide polymorphism (SNP) associations with ASD, reported in previously published genomewide association studies, were selected using a nominal cutoff value of P less than 1.0×10. We tested whether these five SNPs were associated with total AQ and the subscales, after adjustment for possible confounders. SNP rs4141463 located in the macro domain containing 2 (MACROD2) gene was significantly associated with the Communication/Mindreading subscale. No other SNP was significantly associated with total AQ or the subscales. The MACROD2 gene is a strong positional candidate risk factor for autistic-like traits in the general population.

PMID: 25360606 [PubMed - as supplied by publisher]

Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome.

November 2, 2014 - 6:06am
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Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome.

Genome Med. 2014;6(10):75

Authors: Tian Y, Voineagu I, Paşca SP, Won H, Chandran V, Horvath S, Dolmetsch RE, Geschwind DH

Abstract
BACKGROUND: Common genetic variation and rare mutations in genes encoding calcium channel subunits have pleiotropic effects on risk for multiple neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. To gain further mechanistic insights by extending previous gene expression data, we constructed co-expression networks in Timothy syndrome (TS), a monogenic condition with high penetrance for ASD, caused by mutations in the L-type calcium channel, Cav1.2.
METHODS: To identify patient-specific alterations in transcriptome organization, we conducted a genome-wide weighted co-expression network analysis (WGCNA) on neural progenitors and neurons from multiple lines of induced pluripotent stem cells (iPSC) derived from normal and TS (G406R in CACNA1C) individuals. We employed transcription factor binding site enrichment analysis to assess whether TS associated co-expression changes reflect calcium-dependent co-regulation.
RESULTS: We identified reproducible developmental and activity-dependent gene co-expression modules conserved in patient and control cell lines. By comparing cell lines from case and control subjects, we also identified co-expression modules reflecting distinct aspects of TS, including intellectual disability and ASD-related phenotypes. Moreover, by integrating co-expression with transcription factor binding analysis, we showed the TS-associated transcriptional changes were predicted to be co-regulated by calcium-dependent transcriptional regulators, including NFAT, MEF2, CREB, and FOXO, thus providing a mechanism by which altered Ca(2+) signaling in TS patients leads to the observed molecular dysregulation.
CONCLUSIONS: We applied WGCNA to construct co-expression networks related to neural development and depolarization in iPSC-derived neural cells from TS and control individuals for the first time. These analyses illustrate how a systems biology approach based on gene networks can yield insights into the molecular mechanisms of neural development and function, and provide clues as to the functional impact of the downstream effects of Ca(2+) signaling dysregulation on transcription.

PMID: 25360157 [PubMed]

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

November 2, 2014 - 6:06am
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Exploring inhibitory deficits in female premutation carriers of fragile X syndrome: through eye movements.

Brain Cogn. 2014 Mar;85:201-8

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

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

PMID: 24424424 [PubMed - indexed for MEDLINE]

Decoding the contribution of dopaminergic genes and pathways to autism spectrum disorder (ASD).

November 2, 2014 - 6:06am
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Decoding the contribution of dopaminergic genes and pathways to autism spectrum disorder (ASD).

Neurochem Int. 2014 Jan;66:15-26

Authors: Nguyen M, Roth A, Kyzar EJ, Poudel MK, Wong K, Stewart AM, Kalueff AV

Abstract
Autism spectrum disorder (ASD) is a debilitating brain illness causing social deficits, delayed development and repetitive behaviors. ASD is a heritable neurodevelopmental disorder with poorly understood and complex etiology. The central dopaminergic system is strongly implicated in ASD pathogenesis. Genes encoding various elements of this system (including dopamine receptors, the dopamine transporter or enzymes of synthesis and catabolism) have been linked to ASD. Here, we comprehensively evaluate known molecular interactors of dopaminergic genes, and identify their potential molecular partners within up/down-steam signaling pathways associated with dopamine. These in silico analyses allowed us to construct a map of molecular pathways, regulated by dopamine and involved in ASD. Clustering these pathways reveals groups of genes associated with dopamine metabolism, encoding proteins that control dopamine neurotransmission, cytoskeletal processes, synaptic release, Ca(2+) signaling, as well as the adenosine, glutamatergic and gamma-aminobutyric systems. Overall, our analyses emphasize the important role of the dopaminergic system in ASD, and implicate several cellular signaling processes in its pathogenesis.

PMID: 24412511 [PubMed - indexed for MEDLINE]

Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders.

November 2, 2014 - 6:06am
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Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders.

Hum Mol Genet. 2014 Mar 15;23(6):1563-78

Authors: Zhu L, Wang X, Li XL, Towers A, Cao X, Wang P, Bowman R, Yang H, Goldstein J, Li YJ, Jiang YH

Abstract
The molecular basis for the majority of cases of autism spectrum disorders (ASD) remains unknown. We tested the hypothesis that ASD have an epigenetic cause by performing DNA methylation profiling of five CpG islands (CGI-1 to CGI-5) in the SHANK3 gene in postmortem brain tissues from 54 ASD patients and 43 controls. We found significantly increased overall DNA methylation (epimutation) in three intragenic CGIs (CGI-2, CGI-3 and CGI-4). The increased methylation was clustered in the CGI-2 and CGI-4 in ∼15% of ASD brain tissues. SHANK3 has an extensive array of mRNA splice variants resulting from combinations of five intragenic promoters and alternative splicing of coding exons. Altered expression and alternative splicing of SHANK3 isoforms were observed in brain tissues with increased methylation of SHANK3 CGIs in ASD brain tissues. A DNA methylation inhibitor modified the methylation of CGIs and altered the isoform-specific expression of SHANK3 in cultured cells. This study is the first to find altered methylation patterns in SHANK3 in ASD brain samples. Our finding provides evidence to support an alternative approach to investigating the molecular basis of ASD. The ability to alter the epigenetic modification and expression of SHANK3 by environmental factors suggests that SHANK3 may be a valuable biomarker for dissecting the role of gene and environment interaction in the etiology of ASD.

PMID: 24186872 [PubMed - indexed for MEDLINE]

Cerebral visual impairment, autism, and pancreatitis associated with a 9 Mbp deletion on 10p12.

October 31, 2014 - 9:38am
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Cerebral visual impairment, autism, and pancreatitis associated with a 9 Mbp deletion on 10p12.

Clin Dysmorphol. 2014 Oct 29;

Authors: Bosch DG, Boonstra FN, Pfundt R, Cremers FP, de Vries BB

PMID: 25356883 [PubMed - as supplied by publisher]

Nonsyndromic types of ichthyoses - an update.

October 31, 2014 - 9:38am
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Nonsyndromic types of ichthyoses - an update.

J Dtsch Dermatol Ges. 2014 Feb;12(2):109-21

Authors: Traupe H, Fischer J, Oji V

Abstract
Ichthyoses are genetically determined Mendelian disorders of cornification (MEDOC) that are characterized by universal scaling. Today we distinguish between non-syndromic and syndromic forms. Ichthyosis vulgaris is the most frequent type (prevalence 1:100) and is caused by autosomal semi-dominant filaggrin mutations. It is associated with a higher risk for the development of atopic diseases, such as atopic eczema and allergic rhinitis. Recessive X-linked ichthyosis (RXLI) occurs almost exclusively in boys; in Germany it has a prevalence of around 1:4,000. It is caused by steroid sulfatase deficiency and is often associated with further clinical problems, such as cryptorchidism (∼20%) or social communication deficits, such as attention deficit hyperactivity syndrome (40%) or autism (25%). Autosomal recessive congenital ichthyosis (ARCI) is genetically very heterogeneous and 8 different genes have been identified so far. The most frequent cause of ARCI is a transglutaminase 1 deficiency (prevalence 1:200, 000). Mutations in keratin genes are the cause of the keratinopathic ichthyoses, such as epidermolytic ichthyosis. They manifest at birth and often feature episodes of blistering. Most of these types are inherited as autosomal dominant traits, but autosomal recessive forms have also been described on occasion.

PMID: 24119255 [PubMed - indexed for MEDLINE]

Evaluation of the Affymetrix CytoScan Dx assay for developmental delay.

October 29, 2014 - 8:24am

Evaluation of the Affymetrix CytoScan Dx assay for developmental delay.

Expert Rev Mol Diagn. 2014 Oct 28;:1-8

Authors: Webb BD, Scharf RJ, Spear EA, Edelmann LJ, Stroustrup A

Abstract
The goal of molecular cytogenetic testing for children presenting with developmental delay (DD) is to identify or exclude genetic abnormalities that are associated with cognitive, behavioral and/or motor symptoms. Until 2010, chromosome analysis was the standard first-line genetic screening test for evaluation of patients with DD when a specific syndrome was not suspected. In 2010, The American College of Medical Genetics and several other groups recommended chromosomal microarray as the first-line test in children with DDs, multiple congenital anomalies and/or autism. This test is able to detect regions of genomic imbalances at a much finer resolution than G-banded karyotyping. Until recently, no chromosomal microarray testing had been approved by the US FDA. This article focuses on the use of the Affymetrix CytoScan(®) Dx Assay (Santa Clara, CA, USA), the first chromosomal microarray to receive FDA approval for the genetic evaluation of individuals with DD.

PMID: 25350348 [PubMed - as supplied by publisher]

Analysis of FMR1 deletion in a subpopulation of post-mitotic neurons in mouse cortex and hippocampus.

October 29, 2014 - 8:24am
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Analysis of FMR1 deletion in a subpopulation of post-mitotic neurons in mouse cortex and hippocampus.

Autism Res. 2014 Feb;7(1):60-71

Authors: Amiri A, Sanchez-Ortiz E, Cho W, Birnbaum SG, Xu J, McKay RM, Parada LF

Abstract
Fragile X syndrome (FXS) is the most common form of inherited mental retardation and the leading cause of autism. FXS is caused by mutation in a single gene, FMR1, which encodes an RNA-binding protein FMRP. FMRP is highly expressed in neurons and is hypothesized to have a role in synaptic structure, function, and plasticity by regulating mRNAs that encode pre- and post-synaptic proteins. Fmr1 knockout (KO) mice have been used as a model to study FXS. These mice have been reported to show a great degree of phenotypic variability based on the genetic background, environmental signals, and experimental methods. In this study, we sought to restrict FMRP deletion to two brain regions that have been implicated in FXS and autism. We show that ablating Fmr1 in differentiated neurons of hippocampus and cortex results in dendritic alterations and changes in synaptic marker intensity that are brain region specific. In our conditional mutant mice, FMRP-deleted neurons have activated AKT-mTOR pathway signaling in hippocampus but display no apparent behavioral phenotypes. These results highlight the importance of identifying additional factors that interact with Fmr1 to develop FXS.

PMID: 24408886 [PubMed - indexed for MEDLINE]

Evidence for interaction between markers in GABA(A) receptor subunit genes in an Argentinean autism spectrum disorder population.

October 29, 2014 - 8:24am
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Evidence for interaction between markers in GABA(A) receptor subunit genes in an Argentinean autism spectrum disorder population.

Autism Res. 2014 Feb;7(1):162-6

Authors: Sesarini CV, Costa L, Naymark M, Grañana N, Cajal AR, García Coto M, Pallia RC, Argibay PF

Abstract
Autism spectrum disorders (ASD) can be conceptualized as a genetic dysfunction that disrupts development and function of brain circuits mediating social cognition and language. At least some forms of ASD may be associated with high level of excitation in neural circuits, and gamma-aminobutyric acid (GABA) has been implicated in its etiology. Single-nucleotide polymorphisms (SNP) located within the GABA receptor (GABAR) subunit genes GABRA1, GABRG2, GABRB3, and GABRD were screened. A hundred and thirty-six Argentinean ASD patients and 150 controls were studied, and the contribution of the SNPs in the etiology of ASD was evaluated independently and/or through gene-gene interaction using multifactor dimensionality reduction (MDR) method. From the 18 SNP studied, 11 were not present in our Argentinean population (patients and controls) and 1 SNP had minor allele frequency < 0.1%. For the remaining six SNPs, none provided statistical significant association with ASD when considering allelic or genotypic frequencies. Non-significant association with ASD was found for the haplotype analysis. MDR identified evidence for synergy between markers in GABRB3 (chromosome 15) and GABRD (chromosome 1), suggesting potential gene-gene interaction across chromosomes associated with increased risk for autism (testing balanced accuracy: 0.6081 and cross-validation consistency: 10/10, P < 0.001). Considering our Argentinean ASD sample, it can be inferred that GABRB3 would be involved in the etiology of autism through interaction with GABRD. These results support the hypothesis that GABAR subunit genes are involved in autism, most likely via complex gene-gene interactions.

PMID: 24249596 [PubMed - indexed for MEDLINE]

Rare single nucleotide polymorphisms in the regulatory regions of the superoxide dismutase genes in autism spectrum disorder.

October 29, 2014 - 8:24am
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Rare single nucleotide polymorphisms in the regulatory regions of the superoxide dismutase genes in autism spectrum disorder.

Autism Res. 2014 Feb;7(1):138-44

Authors: Kovač J, Macedoni Lukšič M, Trebušak Podkrajšek K, Klančar G, Battelino T

Abstract
Oxidative stress is suspected to be one of the several contributing factors in the etiology of autism spectrum disorder (ASD). We analyzed genes of the superoxide dismutase family (SOD1, SOD2, and SOD3) that are part of a major antioxidative stress system in human in order to detect the genetic variants contributing to the development of ASD. Using the optimized high-resolution melting (HRM) analysis, we identified two rare single nucleotide polymorphisms (SNPs) associated with the etiology of ASD. Both are located in the superoxide dismutase 1 (SOD1) gene and have a minor allele frequency in healthy population ~5%. The SNP c.239 + 34A>C (rs2234694) and SNP g.3341C>G (rs36233090) were detected with an odds ratio of 2.65 and P < 0.01. Both are located in the noncoding potentially regulatory regions of the SOD1 gene. This adds to the importance of rare SNPs in the etiology of complex diseases as well as to the importance of noncoding genetic variants analysis with a potential influence on the regulation of gene expression.

PMID: 24155217 [PubMed - indexed for MEDLINE]

Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci.

October 29, 2014 - 8:24am
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Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci.

Clin Genet. 2013 Dec;84(6):560-5

Authors: Chilian B, Abdollahpour H, Bierhals T, Haltrich I, Fekete G, Nagel I, Rosenberger G, Kutsche K

Abstract
Synaptopathies constitute a group of neurological diseases including autism spectrum disorders (ASD) and intellectual disability (ID). They have been associated with mutations in genes encoding proteins important for the formation and stabilization of synapses, such as SHANK1-3. Loss-of-function mutations in the SHANK genes have been identified in individuals with ASD and ID suggesting that other factors modify the neurological phenotype. We report a boy with severe ID, behavioral anomalies, and language impairment who carries a balanced de novo triple translocation 46,XY,t(11;17;19)(q13.3;q25.1;q13.42). The 11q13.3 breakpoint was found to disrupt the SHANK2 gene. The patient also carries copy number variations at 15q13.3 and 10q22.11 encompassing ARHGAP11B and two synaptic genes. The CHRNA7 gene encoding α7-nicotinic acetylcholine receptor subunit and the GPRIN2 gene encoding G-protein-regulated inducer of neurite growth 2 were duplicated. Co-occurrence of a de novo SHANK2 mutation and a CHRNA7 duplication in two reported patients with ASD and ID as well as in the patient with t(11;17;19), severe ID and behavior problems suggests convergence of these genes on a common synaptic pathway. Our results strengthen the oligogenic inheritance model and highlight the presence of a large effect mutation and modifier genes collectively determining phenotypic expression of the synaptopathy.

PMID: 23350639 [PubMed - indexed for MEDLINE]

Fragile X syndrome: clinical, cytogenetic and molecular screening among autism spectrum disorder children in Indonesia.

October 29, 2014 - 8:24am
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Fragile X syndrome: clinical, cytogenetic and molecular screening among autism spectrum disorder children in Indonesia.

Clin Genet. 2013 Dec;84(6):577-80

Authors: Winarni TI, Utari A, Mundhofir FE, Hagerman RJ, Faradz SM

Abstract
Fragile X testing is a priority in the evaluation of autism spectrum disorders (ASD) cases because identification of the FMR1 mutation leads to new treatment options. This study is focused on determining the prevalence of the FMR1 gene mutation among ASD cases in Indonesia. DSM-IV-TR criteria were administered to diagnose ASD; symptom severity was classified using the Childhood Autism Rating Scale. Cytogenetic analysis, polymerase chain reaction, and Southern blot for FMR1 gene analysis were carried out to confirm the diagnosis of fragile X syndrome. The fragile X site and FMR1 full mutation allele were identified in 3 out of 65 (4.6%) and 4 out of 65 (6.15%) children aged 3-17 years (57 boys and 8 girls), respectively. The Fragile X laboratory workup is essential in the evaluation of patients with ASD. Molecular analysis is most accurate, while cytogenetic documentation of the fragile X site can also be useful if molecular testing is not available.

PMID: 23320543 [PubMed - indexed for MEDLINE]

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