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Obsessive-Compulsive Disorder and Autism Spectrum Disorders: Longitudinal and Offspring Risk.

June 14, 2016 - 9:17am
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Obsessive-Compulsive Disorder and Autism Spectrum Disorders: Longitudinal and Offspring Risk.

PLoS One. 2015;10(11):e0141703

Authors: Meier SM, Petersen L, Schendel DE, Mattheisen M, Mortensen PB, Mors O

Abstract
BACKGROUND: Despite substantial similarities and overlaps in the pathophysiology of obsessive-compulsive disorders (OCD) and autism spectrum disorders, little is known about the clinical and etiologic cohesion of these two disorders. We therefore aimed to determine the patterns of comorbidity, longitudinal risks, and shared familial risks between these disorders.
METHODS: In a prospective study design we explored the effect of a prior diagnosis of OCD in patients and parents on the susceptibility to autism spectrum disorders and vice versa. Analyses were adjusted for sex, age, calendar year, parental age and place at residence at time of birth. As measures of relative risk incidence rate ratios (IRR) and accompanying 95% confidence intervals (CIs) were employed.
RESULTS: The risk of a comorbid diagnosis of OCD in individuals with autism spectrum disorder and aggregation of autism spectrum disorders in offspring of parents with OCD were increased. Individuals first diagnosed with autism spectrum disorders had a 2-fold higher risk of a later diagnosis of OCD (IRR = 2.18, 95% CI = 1.91-2.48), whereas individuals diagnosed with OCD displayed a nearly 4-fold higher risk to be diagnosed with autism spectrum disorders (IRR = 3.91, 95% CI = 3.46-4.40) later in life. The observed associations were somewhat stronger for less severe types of autism spectrum disorders without a comorbid diagnosis of mental disabilities.
CONCLUSIONS: The high comorbidity, sequential risk, and shared familial risks between OCD and autism spectrum disorders are suggestive of partially shared etiological mechanisms. The results have implications for current gene-searching efforts and for clinical practice.

PMID: 26558765 [PubMed - indexed for MEDLINE]

17p11.2 and Xq28 duplication detected in a girl diagnosed with Potocki-Lupski syndrome.

June 14, 2016 - 9:17am
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17p11.2 and Xq28 duplication detected in a girl diagnosed with Potocki-Lupski syndrome.

BMC Res Notes. 2015;8:506

Authors: Sumathipala DS, Mandawala EN, Sumanasena SP, Dissanayake VH

Abstract
BACKGROUND: Potocki-Lupski syndrome is a microduplication syndrome associated with duplication at 17p11.2. Features include facial dysmorphism, moderate to mild cognitive impairment and behavioural abnormalities including autism spectrum disorders.
CASE PRESENTATION: We describe a patient from Sri Lanka that was referred for genetic assessment at 4 years of age due to subtle facial dysmorphism and expressive language impairment. She was diagnosed with Potocki-Lupski syndrome through multiplex ligation probe amplification. She carried two duplications; one in 17p11.2 consistent with Potocki-Lupski, and one in Xq including the region for X-linked intellectual disability.
CONCLUSION: Despite the absence of expected behavioural symptoms, many features of this patient are in accordance with Potocki-Lupski syndrome. This is the first diagnosed patient in Sri Lanka.

PMID: 26419729 [PubMed - indexed for MEDLINE]

Mutations in ARID2 are associated with intellectual disabilities.

June 14, 2016 - 9:17am
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Mutations in ARID2 are associated with intellectual disabilities.

Neurogenetics. 2015 Oct;16(4):307-14

Authors: Shang L, Cho MT, Retterer K, Folk L, Humberson J, Rohena L, Sidhu A, Saliganan S, Iglesias A, Vitazka P, Juusola J, O'Donnell-Luria AH, Shen Y, Chung WK

Abstract
The etiology of intellectual disabilities (ID) remains unknown for the majority of patients. Due to reduced reproductive fitness in many individuals with ID, de novo mutations account for a significant portion of severe ID. The ATP-dependent SWI/SNF chromatin modifier has been linked with neurodevelopmental disorders including ID and autism. ARID2 is an intrinsic component of polybromo-associated BAF (PBAF), the SWI/SNF subcomplex. In this study, we used clinical whole exome sequencing (WES) in proband-parent-trios to identify the etiology of ID. We identified four independent, novel, loss of function variants in ARID2 gene in four patients, three of which were confirmed to be de novo. The patients all have ID and share other clinical characteristics including attention deficit hyperactivity disorder, short stature, dysmorphic facial features, and Wormian bones. All four novel variants are predicted to lead to a premature termination with the loss of the two conservative zinc finger motifs. This is the first report of mutations in ARID2 associated with developmental delay and ID.

PMID: 26238514 [PubMed - indexed for MEDLINE]

Current knowledge on the genetics of autism and propositions for future research.

June 13, 2016 - 6:07am

Current knowledge on the genetics of autism and propositions for future research.

C R Biol. 2016 Jun 8;

Authors: Bourgeron T

Abstract
Autism spectrum disorders (ASD) are a heterogeneous group of neuropsychiatric disorders characterized by problems in social communication, as well as by the presence of restricted interests, stereotyped and repetitive behaviours. In the last 40years, genetic studies have provided crucial information on the causes of ASD and its diversity. In this article, I will first review the current knowledge on the genetics of ASD and then suggest three propositions to foster research in this field. Twin and familial studies estimated the heritability of ASD to be 50%. While most of the inherited part of ASD is captured by common variants, our current knowledge on the genetics of ASD comes almost exclusively from the identification of highly penetrant de novo mutations through candidate gene or whole exome/genome sequencing studies. Approximately 10% of patients with ASD, especially those with intellectual disability, are carriers of de novo copy-number (CNV) or single nucleotide variants (SNV) affecting clinically relevant genes for ASD. Given the function of these genes, it was hypothesized that abnormal synaptic plasticity and failure of neuronal/synaptic homeostasis could increase the risk of ASD. In addition to these discoveries, three propositions coming from institutions, researchers and/or communities of patients and families can be made to foster research on ASD: (i) to use more dimensional and quantitative data than diagnostic categories; (ii) to increase data sharing and research on genetic and brain diversity in human populations; (iii) to involve patients and relatives as participants for research. Hopefully, this knowledge will lead to a better diagnosis, care and integration of individuals with ASD.

PMID: 27289453 [PubMed - as supplied by publisher]

Autism spectrum disorder prevalence and proximity to industrial facilities releasing arsenic, lead or mercury.

June 11, 2016 - 6:03am
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Autism spectrum disorder prevalence and proximity to industrial facilities releasing arsenic, lead or mercury.

Sci Total Environ. 2015 Dec 1;536:245-51

Authors: Dickerson AS, Rahbar MH, Han I, Bakian AV, Bilder DA, Harrington RA, Pettygrove S, Durkin M, Kirby RS, Wingate MS, Tian LH, Zahorodny WM, Pearson DA, Moyé LA, Baio J

Abstract
Prenatal and perinatal exposures to air pollutants have been shown to adversely affect birth outcomes in offspring and may contribute to prevalence of autism spectrum disorder (ASD). For this ecologic study, we evaluated the association between ASD prevalence, at the census tract level, and proximity of tract centroids to the closest industrial facilities releasing arsenic, lead or mercury during the 1990s. We used 2000 to 2008 surveillance data from five sites of the Autism and Developmental Disabilities Monitoring (ADDM) network and 2000 census data to estimate prevalence. Multi-level negative binomial regression models were used to test associations between ASD prevalence and proximity to industrial facilities in existence from 1991 to 1999 according to the US Environmental Protection Agency Toxics Release Inventory (USEPA-TRI). Data for 2489 census tracts showed that after adjustment for demographic and socio-economic area-based characteristics, ASD prevalence was higher in census tracts located in the closest 10th percentile compared of distance to those in the furthest 50th percentile (adjusted RR=1.27, 95% CI: (1.00, 1.61), P=0.049). The findings observed in this study are suggestive of the association between urban residential proximity to industrial facilities emitting air pollutants and higher ASD prevalence.

PMID: 26218563 [PubMed - indexed for MEDLINE]

Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca(2+)-dependent inactivation.

June 10, 2016 - 9:01am
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Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca(2+)-dependent inactivation.

Nat Commun. 2016;7:10370

Authors: Dick IE, Joshi-Mukherjee R, Yang W, Yue DT

Abstract
Timothy Syndrome (TS) is a multisystem disorder, prominently featuring cardiac action potential prolongation with paroxysms of life-threatening arrhythmias. The underlying defect is a single de novo missense mutation in CaV1.2 channels, either G406R or G402S. Notably, these mutations are often viewed as equivalent, as they produce comparable defects in voltage-dependent inactivation and cause similar manifestations in patients. Yet, their effects on calcium-dependent inactivation (CDI) have remained uncertain. Here, we find a significant defect in CDI in TS channels, and uncover a remarkable divergence in the underlying mechanism for G406R versus G402S variants. Moreover, expression of these TS channels in cultured adult guinea pig myocytes, combined with a quantitative ventricular myocyte model, reveals a threshold behaviour in the induction of arrhythmias due to TS channel expression, suggesting an important therapeutic principle: a small shift in the complement of mutant versus wild-type channels may confer significant clinical improvement.

PMID: 26822303 [PubMed - indexed for MEDLINE]

Autism Spectrum Disorders: Translating human deficits into mouse behavior.

June 10, 2016 - 9:01am
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Autism Spectrum Disorders: Translating human deficits into mouse behavior.

Neurobiol Learn Mem. 2015 Oct;124:71-87

Authors: Pasciuto E, Borrie SC, Kanellopoulos AK, Santos AR, Cappuyns E, D'Andrea L, Pacini L, Bagni C

Abstract
Autism Spectrum Disorders are a heterogeneous group of neurodevelopmental disorders, with rising incidence but little effective therapeutic intervention available. Currently two main clinical features are described to diagnose ASDs: impaired social interaction and communication, and repetitive behaviors. Much work has focused on understanding underlying causes of ASD by generating animal models of the disease, in the hope of discovering signaling pathways and cellular targets for drug intervention. Here we review how ASD behavioral phenotypes can be modeled in the mouse, the most common animal model currently in use in this field, and discuss examples of genetic mouse models of ASD with behavioral features that recapitulate various symptoms of ASD.

PMID: 26220900 [PubMed - indexed for MEDLINE]

Genomic Imprinting.

June 9, 2016 - 5:51pm

Genomic Imprinting.

Open Access Maced J Med Sci. 2016 Mar 15;4(1):181-184

Authors: Bajrami E, Spiroski M

Abstract
BACKGROUND: Genomic imprinting is the inheritance out of Mendelian borders. Many of inherited diseases and human development violates Mendelian law of inheritance, this way of inheriting is studied by epigenetics.
AIM: The aim of this review is to analyze current opinions and options regarding to this way of inheriting.
RESULTS: Epigenetics shows that gene expression undergoes changes more complex than modifications in the DNA sequence; it includes the environmental influence on the gametes before conception. Humans inherit two alleles from mother and father, both are functional for the majority of the genes, but sometimes one is turned off or "stamped" and doesn't show in offspring, that gene is imprinted. Imprinting means that that gene is silenced, and gene from other parent is expressed. The mechanisms for imprinting are still incompletely defined, but they involve epigenetic modifications that are erased and then reset during the creation of eggs and sperm. Genomic imprinting is a process of silencing genes through DNA methylation. The repressed allele is methylated, while the active allele is unmethylated. The most well-known conditions include Prader-Willi syndrome, and Angelman syndrome. Both of these syndromes can be caused by imprinting or other errors involving genes on the long arm of chromosome 15.
CONCLUSIONS: Genomic imprinting and other epigenetic mechanisms such as environment is shown that plays role in offspring neurodevelopment and autism spectrum disorder.

PMID: 27275355 [PubMed - as supplied by publisher]

Diagnostic yield of array CGH in patients with autism spectrum disorder in Hong Kong.

June 9, 2016 - 5:51pm

Diagnostic yield of array CGH in patients with autism spectrum disorder in Hong Kong.

Clin Transl Med. 2016 Dec;5(1):18

Authors: Siu WK, Lam CW, Mak CM, Lau ET, Tang MH, Tang WF, Poon-Mak RS, Lee CC, Hung SF, Leung PW, Kwong KL, Yau EK, Ng GS, Fong NC, Chan KY

Abstract
BACKGROUND: Chromosomal microarray offers superior sensitivity for identification of submicroscopic copy number variants (CNV) and it is advocated to be the first tier genetic testing for patients with autism spectrum disorder (ASD). In this regard, diagnostic yield of array comparative genomic hybridization (CGH) for ASD patients is determined in a cohort of Chinese patients in Hong Kong.
METHODS: A combined adult and paediatric cohort of 68 Chinese ASD patients (41 patients in adult group and 27 patients in paediatric group). The genomic DNA extracted from blood samples were analysed by array CGH using NimbleGen CGX-135K oligonucleotide array.
RESULTS: We identified 15 CNV and eight of them were clinically significant. The overall diagnostic yield was 11.8 %. Five clinically significant CNV were detected in the adult group and three were in the paediatric group, providing diagnostic yields of 12.2 and 11.1 % respectively. The most frequently detected CNV was 16p13.11 duplications which were present in 4 patients (5.9 % of the cohort).
CONCLUSIONS: In this study, a satisfactory diagnostic yield of array CGH was demonstrated in a Chinese ASD patient cohort which supported the clinical usefulness of array CGH as the first line testing of ASD in Hong Kong.

PMID: 27271878 [PubMed - as supplied by publisher]

Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons.

June 9, 2016 - 5:51pm
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Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons.

Science. 2016 May 6;352(6286):aaf2669

Authors: Yi F, Danko T, Botelho SC, Patzke C, Pak C, Wernig M, Südhof TC

Abstract
Heterozygous SHANK3 mutations are associated with idiopathic autism and Phelan-McDermid syndrome. SHANK3 is a ubiquitously expressed scaffolding protein that is enriched in postsynaptic excitatory synapses. Here, we used engineered conditional mutations in human neurons and found that heterozygous and homozygous SHANK3 mutations severely and specifically impaired hyperpolarization-activated cation (Ih) channels. SHANK3 mutations caused alterations in neuronal morphology and synaptic connectivity; chronic pharmacological blockage of Ih channels reproduced these phenotypes, suggesting that they may be secondary to Ih-channel impairment. Moreover, mouse Shank3-deficient neurons also exhibited severe decreases in Ih currents. SHANK3 protein interacted with hyperpolarization-activated cyclic nucleotide-gated channel proteins (HCN proteins) that form Ih channels, indicating that SHANK3 functions to organize HCN channels. Our data suggest that SHANK3 mutations predispose to autism, at least partially, by inducing an Ih channelopathy that may be amenable to pharmacological intervention.

PMID: 26966193 [PubMed - indexed for MEDLINE]

Identification of Males with Cryptic Fragile X Alleles by Methylation-Specific Quantitative Melt Analysis.

June 9, 2016 - 5:51pm
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Identification of Males with Cryptic Fragile X Alleles by Methylation-Specific Quantitative Melt Analysis.

Clin Chem. 2016 Feb;62(2):343-52

Authors: Aliaga SM, Slater HR, Francis D, Du Sart D, Li X, Amor DJ, Alliende AM, Santa Maria L, Faundes V, Morales P, Trigo C, Salas I, Curotto B, Godler DE

Abstract
BACKGROUND: FMR1 full mutations (FMs) (CGG expansion >200) in males mosaic for a normal (<45 CGG) or gray-zone (GZ) (45-54 CGG) allele can be missed with the standard 2-step fragile X syndrome (FXS) testing protocols, largely because the first-line PCR tests showing a normal or GZ allele are not reflexed to the second-line test that can detect FM.
METHODS: We used methylation-specific quantitative melt analysis (MS-QMA) to determine the prevalence of cryptic FM alleles in 2 independent cohorts of male patients (994 from Chile and 2392 from Australia) referred for FXS testing from 2006 to 2013. All MS-QMA-positive cases were retested with commercial triplet primed PCR, methylation-sensitive Southern blot, and a methylation-specific EpiTYPER-based test.
RESULTS: All 38 FMs detected with the standard 2-step protocol were detected with MS-QMA. However, MS-QMA identified methylation mosaicism in an additional 15% and 11% of patients in the Chilean and Australian cohorts, respectively, suggesting the presence of a cryptic FM. Of these additional patients, 57% were confirmed to carry cryptic expanded alleles in blood, buccal mucosa, or saliva samples. Further confirmation was provided by identifying premutation (CGG 55-199) alleles in mothers of probands with methylation-sensitive Southern blot. Neurocognitive assessments showed that low-level mosaicism for cryptic FM alleles was associated with cognitive impairment or autism.
CONCLUSIONS: A substantial number of mosaic FM males who have cognitive impairment or autism are not diagnosed with the currently recommended 2-step testing protocol and can be identified with MS-QMA as a first-line test.

PMID: 26715660 [PubMed - indexed for MEDLINE]

Peroxisomes in brain development and function.

June 9, 2016 - 5:51pm
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Peroxisomes in brain development and function.

Biochim Biophys Acta. 2016 May;1863(5):934-55

Authors: Berger J, Dorninger F, Forss-Petter S, Kunze M

Abstract
Peroxisomes contain numerous enzymatic activities that are important for mammalian physiology. Patients lacking either all peroxisomal functions or a single enzyme or transporter function typically develop severe neurological deficits, which originate from aberrant development of the brain, demyelination and loss of axonal integrity, neuroinflammation or other neurodegenerative processes. Whilst correlating peroxisomal properties with a compilation of pathologies observed in human patients and mouse models lacking all or individual peroxisomal functions, we discuss the importance of peroxisomal metabolites and tissue- and cell type-specific contributions to the observed brain pathologies. This enables us to deconstruct the local and systemic contribution of individual metabolic pathways to specific brain functions. We also review the recently discovered variability of pathological symptoms in cases with unexpectedly mild presentation of peroxisome biogenesis disorders. Finally, we explore the emerging evidence linking peroxisomes to more common neurological disorders such as Alzheimer's disease, autism and amyotrophic lateral sclerosis.

PMID: 26686055 [PubMed - indexed for MEDLINE]

Human Neuropsychiatric Disease Modeling using Conditional Deletion Reveals Synaptic Transmission Defects Caused by Heterozygous Mutations in NRXN1.

June 9, 2016 - 5:51pm
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Human Neuropsychiatric Disease Modeling using Conditional Deletion Reveals Synaptic Transmission Defects Caused by Heterozygous Mutations in NRXN1.

Cell Stem Cell. 2015 Sep 3;17(3):316-28

Authors: Pak C, Danko T, Zhang Y, Aoto J, Anderson G, Maxeiner S, Yi F, Wernig M, Südhof TC

Abstract
Heterozygous mutations of the NRXN1 gene, which encodes the presynaptic cell-adhesion molecule neurexin-1, were repeatedly associated with autism and schizophrenia. However, diverse clinical presentations of NRXN1 mutations in patients raise the question of whether heterozygous NRXN1 mutations alone directly impair synaptic function. To address this question under conditions that precisely control for genetic background, we generated human ESCs with different heterozygous conditional NRXN1 mutations and analyzed two different types of isogenic control and NRXN1 mutant neurons derived from these ESCs. Both heterozygous NRXN1 mutations selectively impaired neurotransmitter release in human neurons without changing neuronal differentiation or synapse formation. Moreover, both NRXN1 mutations increased the levels of CASK, a critical synaptic scaffolding protein that binds to neurexin-1. Our results show that, unexpectedly, heterozygous inactivation of NRXN1 directly impairs synaptic function in human neurons, and they illustrate the value of this conditional deletion approach for studying the functional effects of disease-associated mutations.

PMID: 26279266 [PubMed - indexed for MEDLINE]

Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications.

June 9, 2016 - 5:51pm
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Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications.

Brain Behav Immun. 2015 Oct;49:197-205

Authors: Chana G, Laskaris L, Pantelis C, Gillett P, Testa R, Zantomio D, Burrows EL, Hannan AJ, Everall IP, Skafidas E

Abstract
Metabotropic glutamate receptor 5 (mGluR5) and microglial abnormalities have been implicated in autism spectrum disorder (ASD). However, controversy exists as to whether the receptor is down or upregulated in functioning in ASD. In addition, whilst activation of mGluR5 has been shown to attenuate microglial activation, its role in maintaining microglial homeostasis during development has not been investigated. We utilised published microarray data from the dorsolateral prefrontal cortex (DLPFC) of control (n=30) and ASD (n=27) individuals to carry out regression analysis to assess gene expression of mGluR5 downstream signalling elements. We then conducted a post-mortem brain stereological investigation of the DLPFC, to estimate the proportion of mGluR5-positive neurons and glia. Finally, we carried out stereological investigation into numbers of microglia in mGluR5 knockout mice, relative to wildtype littermates, together with assessment of changes in microglial somal size, as an indicator of activation status. We found that gene expression of mGluR5 was significantly decreased in ASD versus controls (p=0.018) as well as downstream elements SHANK3 (p=0.005) and PLCB1 (p=0.009) but that the pro-inflammatory marker NOS2 was increased (p=0.047). Intensity of staining of mGluR5-positive neurons was also significantly decreased in ASD versus controls (p=0.016). Microglial density was significantly increased in mGluR5 knockout animals versus wildtype controls (p=0.011). Our findings provide evidence for decreased expression of mGluR5 and its signalling components representing a key pathophysiological hallmark in ASD with implications for the regulation of microglial number and activation during development. This is important in the context of microglia being considered to play key roles in synaptic pruning during development, with preservation of appropriate connectivity relevant for normal brain functioning.

PMID: 26052099 [PubMed - indexed for MEDLINE]

A unique binding mode of the eukaryotic translation initiation factor 4E for guiding the design of novel peptide inhibitors.

June 9, 2016 - 5:51pm
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A unique binding mode of the eukaryotic translation initiation factor 4E for guiding the design of novel peptide inhibitors.

Protein Sci. 2015 Sep;24(9):1370-82

Authors: Di Marino D, D'Annessa I, Tancredi H, Bagni C, Gallicchio E

Abstract
The interaction between the eukaryotic translation initiation factor 4E (eIF4E) and eIF4E binding proteins (4E-BP) is a promising template for the inhibition of eIF4E and the treatment of diseases such as cancer and a spectrum of autism disorders, including the Fragile X syndrome (FXS). Here, we report an atomically detailed model of the complex between eIF4E and a peptide fragment of a 4E-BP, the cytoplasmic Fragile X interacting protein (CYFIP1). This model was generated using computer simulations with enhanced sampling from an alchemical replica exchange approach and validated using long molecular dynamics simulations. 4E-BP proteins act as post-transcriptional regulators by binding to eIF4E and preventing mRNA translation. Dysregulation of eIF4E activity has been linked to cancer, FXS, and autism spectrum disorders. Therefore, the study of the mechanism of inhibition of eIF4E by 4E-BPs is key to the development of drug therapies targeting this regulatory pathways. The results obtained in this work indicate that CYFIP1 interacts with eIF4E by an unique mode not shared by other 4E-BP proteins and elucidate the mechanism by which CYFIP1 interacts with eIF4E despite having a sequence binding motif significantly different from most 4E-BPs. Our study suggests an alternative strategy for the design of eIF4E inhibitor peptides with superior potency and specificity than currently available.

PMID: 26013047 [PubMed - indexed for MEDLINE]

NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse.

June 9, 2016 - 5:51pm
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NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse.

Mol Psychiatry. 2015 Sep;20(9):1120-31

Authors: Schuster S, Rivalan M, Strauss U, Stoenica L, Trimbuch T, Rademacher N, Parthasarathy S, Lajkó D, Rosenmund C, Shoichet SA, Winter Y, Tarabykin V, Rosário M

Abstract
Neuropsychiatric developmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia, are typically characterized by alterations in social behavior and have been linked to aberrant dendritic spine and synapse development. Here we show, using genetically engineered mice, that the Cdc42 GTPase-activating multiadaptor protein, NOMA-GAP, regulates autism-like social behavior in the mouse, as well as dendritic spine and synapse development. Surprisingly, we were unable to restore spine morphology or autism-associated social behavior in NOMA-GAP-deficient animals by Cre-mediated deletion of Cdc42 alone. Spine morphology can be restored in vivo by re-expression of wild-type NOMA-GAP or a mutant of NOMA-GAP that lacks the RhoGAP domain, suggesting that other signaling functions are involved. Indeed, we show that NOMA-GAP directly interacts with several MAGUK (membrane-associated guanylate kinase) proteins, and that this modulates NOMA-GAP activity toward Cdc42. Moreover, we demonstrate that NOMA-GAP is a major regulator of PSD-95 in the neocortex. Loss of NOMA-GAP leads to strong upregulation of serine 295 phosphorylation of PSD-95 and moreover to its subcellular mislocalization. This is associated with marked loss of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and defective synaptic transmission, thereby providing a molecular basis for autism-like social behavior in the absence of NOMA-GAP.

PMID: 25869807 [PubMed - indexed for MEDLINE]

Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.

June 9, 2016 - 5:51pm
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Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.

Mol Psychiatry. 2015 Sep;20(9):1069-78

Authors: Oguro-Ando A, Rosensweig C, Herman E, Nishimura Y, Werling D, Bill BR, Berg JM, Gao F, Coppola G, Abrahams BS, Geschwind DH

Abstract
Rare maternally inherited duplications at 15q11-13 are observed in ~1% of individuals with an autism spectrum disorder (ASD), making it among the most common causes of ASD. 15q11-13 comprises a complex region, and as this copy number variation encompasses many genes, it is important to explore individual genotype-phenotype relationships. Cytoplasmic FMR1-interacting protein 1 (CYFIP1) is of particular interest because of its interaction with Fragile X mental retardation protein (FMRP), its upregulation in transformed lymphoblastoid cell lines from patients with duplications at 15q11-13 and ASD and the presence of smaller overlapping deletions of CYFIP1 in patients with schizophrenia and intellectual disability. Here, we confirm that CYFIP1 is upregulated in transformed lymphoblastoid cell lines and demonstrate its upregulation in the post-mortem brain from 15q11-13 duplication patients for the first time. To investigate how increased CYFIP1 dosage might predispose to neurodevelopmental disease, we studied the consequence of its overexpression in multiple systems. We show that overexpression of CYFIP1 results in morphological abnormalities including cellular hypertrophy in SY5Y cells and differentiated mouse neuronal progenitors. We validate these results in vivo by generating a BAC transgenic mouse, which overexpresses Cyfip1 under the endogenous promotor, observing an increase in the proportion of mature dendritic spines and dendritic spine density. Gene expression profiling on embryonic day 15 suggested the dysregulation of mammalian target of rapamycin (mTOR) signaling, which was confirmed at the protein level. Importantly, similar evidence of mTOR-related dysregulation was seen in brains from 15q11-13 duplication patients with ASD. Finally, treatment of differentiated mouse neuronal progenitors with an mTOR inhibitor (rapamycin) rescued the morphological abnormalities resulting from CYFIP1 overexpression. Together, these data show that CYFIP1 overexpression results in specific cellular phenotypes and implicate modulation by mTOR signaling, further emphasizing its role as a potential convergent pathway in some forms of ASD.

PMID: 25311365 [PubMed - indexed for MEDLINE]

Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.

June 9, 2016 - 5:51pm
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Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.

Mol Psychiatry. 2015 Sep;20(9):1132-8

Authors: Frazier TW, Embacher R, Tilot AK, Koenig K, Mester J, Eng C

Abstract
PTEN is a tumor suppressor associated with an inherited cancer syndrome and an important regulator of ongoing neural connectivity and plasticity. The present study examined molecular and phenotypic characteristics of individuals with germline heterozygous PTEN mutations and autism spectrum disorder (ASD) (PTEN-ASD), with the aim of identifying pathophysiologic markers that specifically associate with PTEN-ASD and that may serve as targets for future treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14). Group differences were evaluated for PTEN pathway protein expression levels, global and regional structural brain volumes and cortical thickness measures, neurocognition and adaptive behavior. RNA expression patterns and brain characteristics of a murine model of Pten mislocalization were used to further evaluate abnormalities observed in human PTEN-ASD patients. PTEN-ASD had a high proportion of missense mutations and showed reduced PTEN protein levels. Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory. White-matter abnormalities mediated the relationship between PTEN protein reductions and reduced cognitive ability. The Pten(m3m4) murine model had differential expression of genes related to myelination and increased corpus callosum. Processing speed and working memory deficits and white-matter abnormalities may serve as useful features that signal clinicians that PTEN is etiologic and prompting referral to genetic professionals for gene testing, genetic counseling and cancer risk management; and could reveal treatment targets in trials of treatments for PTEN-ASD.

PMID: 25288137 [PubMed - indexed for MEDLINE]

Autism, DRD3 and repetitive and stereotyped behavior, an overview of the current knowledge.

June 9, 2016 - 5:51pm
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Autism, DRD3 and repetitive and stereotyped behavior, an overview of the current knowledge.

Eur Neuropsychopharmacol. 2015 Sep;25(9):1421-6

Authors: Staal WG

Abstract
The SNP rs167771 of the dopamine-3-receptor gene (DRD3) has been associated with autism spectrum disorder (ASD) in samples from the United Kingdom, The Netherlands and Spain. The DRD3 polymorphisms of rs167771 are significantly associated with a specific type of repetitive and stereotyped behavior, called sameness. Repetitive and stereotyped behavior occurs in several neuropsychiatric disorders and the combined picture across these disorders strongly suggests the involvement of the basal ganglia - frontal lobe circuitry. In autism, abnormalities of the basal ganglia, in particular the caudate nucleus, are the best replicated findings in neuroimaging studies. Interestingly, the DRD3 gene is highly expressed in the basal ganglia, most notably the caudate nucleus. The rs167771 SNP was recently also found to be related to risperidone-induced extra-pyramidal side effects (EPS) in patients with autism, which is important since risperidone is approved for the treatment of aggression, irritability and rigid behavior in ASD. To conclude, striatum abnormalities in autism are associated with repetitive and stereotyped behavior in autism and may be related to DRD3 polymorphisms.

PMID: 25224105 [PubMed - indexed for MEDLINE]

ELAVL2-regulated transcriptional and splicing networks in human neurons link neurodevelopment and autism.

June 5, 2016 - 8:29am
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ELAVL2-regulated transcriptional and splicing networks in human neurons link neurodevelopment and autism.

Hum Mol Genet. 2016 Jun 3;

Authors: Berto S, Usui N, Konopka G, Fogel BL

Abstract
The role of post-transcriptional gene regulation in human brain development and neurodevelopmental disorders remains mostly uncharacterized. ELAV-like RNA-binding proteins are a family of proteins that regulate several aspects of neuronal function including neuronal excitability and synaptic transmission, both critical to the normal function of the brain in cognition and behavior. Here, we identify the downstream neuronal transcriptional and splicing networks of ELAVL2, an RNA-binding protein with previously unknown function in the brain. Expression of ELAVL2 was reduced in human neurons and RNA-sequencing was utilized to identify networks of differentially expressed and alternatively spliced genes resulting from haploinsufficient levels of ELAVL2. These networks contain a number of autism-relevant genes as well as previously identified targets of other important RNA-binding proteins implicated in autism spectrum disorder including RBFOX1 and FMRP. ELAVL2-regulated co-expression networks are also enriched for neurodevelopmental and synaptic genes, and include genes with human-specific patterns of expression in the frontal pole. Together, these data suggest that ELAVL2 regulation of transcript expression is critical for neuronal function and clinically relevant to autism spectrum disorder.

PMID: 27260404 [PubMed - as supplied by publisher]

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