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STAMS: STRING-Assisted Module Search for Genome Wide Association Studies and Application to Autism.

August 21, 2016 - 8:56am

STAMS: STRING-Assisted Module Search for Genome Wide Association Studies and Application to Autism.

Bioinformatics. 2016 Aug 19;

Authors: Hillenmeyer S, Davis LK, Gamazon ER, Cook EH, Cox NJ, Altman RB

Abstract
MOTIVATION: Analyzing genome wide association data in the context of biological pathways helps us understand how genetic variation influences phenotype and increases power to find associations. However, the utility of pathway-based analysis tools is hampered by undercuration and reliance on a distribution of signal across all of the genes in a pathway. Methods that combine genome wide association results with genetic networks to infer the key phenotype-modulating subnetworks combat these issues, but have primarily been limited to network definitions with yes/no labels for gene-gene interactions. A recent method (EW_dmGWAS) incorporates a biological network with weighted edge probability by requiring a secondary phenotype-specific expression dataset. In this paper, we combine an algorithm for weighted-edge module searching and a probabilistic interaction network in order to develop a method, STAMS, for recovering modules of genes with strong associations to the phenotype and probable biologic coherence. Our method builds on EW_dmGWAS but does not require a secondary expression dataset and performs better in six test cases.
RESULTS: We show that our algorithm improves over EW_dmGWAS and standard gene-based analysis by measuring precision and recall of each method on separately identified associations. In the Wellcome Trust Rheumatoid Arthritis study, STAMS-identified modules were more enriched for separately identified associations than EW_dmGWAS (STAMS p-value 3.0×10(-4); EW_dmGWAS- p-value=0.8). We demonstrate that the area under the Precision-Recall curve is 5.9 times higher with STAMS than EW_dmGWAS run on the Wellcome Trust Type 1 Diabetes data.
AVAILABILITY: STAMS is implemented as an R package and is freely available at https://simtk.org/projects/stams CONTACT: rbaltman@stanford.edu.

PMID: 27542772 [PubMed - as supplied by publisher]

Altered Effects of Perspective-Taking on Functional Connectivity during Self- and Other-Referential Processing in Adults with Autism Spectrum Disorder.

August 20, 2016 - 8:55am

Altered Effects of Perspective-Taking on Functional Connectivity during Self- and Other-Referential Processing in Adults with Autism Spectrum Disorder.

Soc Neurosci. 2016 Aug 18;

Authors: Hashimoto RI, Itahashi T, Ohta H, Yamada T, Kanai C, Nakamura M, Watanabe H, Kato N

Abstract
In interactive social situations, it is often crucial to be able to take another person's perspective when evaluating one's own or another person's specific trait; individuals with ASD critically lack this social skill. To examine how perspective-dependent self- and other-evaluation processes modulate functional connectivity in ASD, we conducted an fMRI study in which 26 high-functioning adults with ASD and 24 typically developed (TD) controls were asked to decide whether an adjective describing a personality trait correctly described the participant himself/herself ("self") or the participant's mother ("other") by taking either the first (1P) or third person (3P) perspective. We observed that functional connectivity between the left sensorimotor cortex and the left middle cingulate cortex was enhanced in TD taking the 3P perspective, this enhancement was significantly reduced in ASD, and the degree of reduction was significantly correlated with the severity of autistic traits. Furthermore, the self-reference effect on functional connectivity between the left inferior frontal cortex and frontopolar cortices was significantly enhanced in TD taking the 3P perspective, whereas such effect was reversed in ASD. These findings indicate altered effects of perspective on the functional connectivity, which may underlie the deficits in social interaction and communication observed in individuals with ASD.

PMID: 27538473 [PubMed - as supplied by publisher]

Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration.

August 20, 2016 - 8:55am
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Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration.

Nat Commun. 2016;7:11173

Authors: Pearson BL, Simon JM, McCoy ES, Salazar G, Fragola G, Zylka MJ

Abstract
Environmental factors, including pesticides, have been linked to autism and neurodegeneration risk using retrospective epidemiological studies. Here we sought to prospectively identify chemicals that share transcriptomic signatures with neurological disorders, by exposing mouse cortical neuron-enriched cultures to hundreds of chemicals commonly found in the environment and on food. We find that rotenone, a pesticide associated with Parkinson's disease risk, and certain fungicides, including pyraclostrobin, trifloxystrobin, famoxadone and fenamidone, produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age and neurodegeneration (Alzheimer's disease and Huntington's disease). These chemicals stimulate free radical production and disrupt microtubules in neurons, effects that can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane. Our study provides an approach to prospectively identify environmental chemicals that transcriptionally mimic autism and other brain disorders.

PMID: 27029645 [PubMed - indexed for MEDLINE]

A Cross-Disorder Method to Identify Novel Candidate Genes for Developmental Brain Disorders.

August 20, 2016 - 8:55am
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A Cross-Disorder Method to Identify Novel Candidate Genes for Developmental Brain Disorders.

JAMA Psychiatry. 2016 Mar;73(3):275-83

Authors: Gonzalez-Mantilla AJ, Moreno-De-Luca A, Ledbetter DH, Martin CL

Abstract
IMPORTANCE: Developmental brain disorders are a group of clinically and genetically heterogeneous disorders characterized by high heritability. Specific highly penetrant genetic causes can often be shared by a subset of individuals with different phenotypic features, and recent advances in genome sequencing have allowed the rapid and cost-effective identification of many of these pathogenic variants.
OBJECTIVES: To identify novel candidate genes for developmental brain disorders and provide additional evidence of previously implicated genes.
DATA SOURCES: The PubMed database was searched for studies published from March 28, 2003, through May 7, 2015, with large cohorts of individuals with developmental brain disorders.
DATA EXTRACTION AND SYNTHESIS: A tiered, multilevel data-integration approach was used, which intersects (1) whole-genome data from structural and sequence pathogenic loss-of-function (pLOF) variants, (2) phenotype data from 6 apparently distinct disorders (intellectual disability, autism, attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorder, and epilepsy), and (3) additional data from large-scale studies, smaller cohorts, and case reports focusing on specific candidate genes. All candidate genes were ranked into 4 tiers based on the strength of evidence as follows: tier 1, genes with 3 or more de novo pathogenic loss-of-function variants; tier 2, genes with 2 de novo pathogenic loss-of-function variants; tier 3, genes with 1 de novo pathogenic loss-of-function variant; and tier 4, genes with only inherited (or unknown inheritance) pathogenic loss-of-function variants.
MAIN OUTCOMES AND MEASURES: Development of a comprehensive knowledge base of candidate genes related to developmental brain disorders. Genes were prioritized based on the inheritance pattern and total number of pathogenic loss-of-function variants identified amongst unrelated individuals with any one of six developmental brain disorders.
STUDY SELECTION: A combination of phenotype-based and genotype-based literature review yielded 384 studies that used whole-genome or exome sequencing, chromosomal microarray analysis, and/or targeted sequencing to evaluate 1960 individuals with developmental brain disorders.
RESULTS: Our initial phenotype-based literature review yielded 1911 individuals with pLOF variants involving 1034 genes from 118 studies. Filtering our results to genes with 2 or more pLOF variants identified in at least 2 unrelated individuals resulted in 241 genes from 1110 individuals. Of the 241 genes involved in brain disorders, 7 were novel high-confidence genes and 10 were novel putative candidate genes. Fifty-nine genes were ranked in tier 1, 44 in tier 2, 68 in tier 3, and 70 in tier 4. By transcending clinical diagnostic boundaries, the evidence level for 18 additional genes that were ranked 1 tier higher because of this cross-disorder approach was increased.
CONCLUSIONS AND RELEVANCE: This approach increased the yield of gene discovery over what would be obtained if each disorder, type of genomic variant, and study design were analyzed independently. These results provide further support for shared genomic causes among apparently different disorders and demonstrate the clinical and genetic heterogeneity of developmental brain disorders.

PMID: 26817790 [PubMed - indexed for MEDLINE]

Five patients with a chromosome 1q21.1 triplication show macrocephaly, increased weight and facial similarities.

August 20, 2016 - 8:55am
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Five patients with a chromosome 1q21.1 triplication show macrocephaly, increased weight and facial similarities.

Eur J Med Genet. 2015 Oct;58(10):503-8

Authors: Van Dijck A, van der Werf IM, Reyniers E, Scheers S, Azage M, Siefkas K, Van der Aa N, Lacroix A, Rosenfeld J, Argiropoulos B, Davis K, Innes AM, Mefford HC, Mortier G, Meuwissen M, Kooy RF

Abstract
Recurrent rearrangements of chromosome 1q21.1 that occur as a consequence of non-allelic homologous recombination (NAHR) show considerable variability in phenotypic expression and penetrance. Chromosome 1q21.1 deletions (OMIM 612474) have been associated with microcephaly, intellectual disability, autism, schizophrenia, cardiac abnormalities and cataracts. Phenotypic features in individuals with 1q21.1 duplications (OMIM 612475) include macrocephaly, learning difficulties, developmental delay, intellectual disability and mild dysmorphic features. Half of these patients show autistic behavior. For the first time, we describe five patients, including monozygotic twins, with a triplication of the 1q21.1 chromosomal segment. Facial features common to all patients include a high, broad forehead; a flat and broad nasal bridge; long, downslanted palpebral fissures and dysplastic, low-set ears. Likely associated features include macrocephaly and increased weight. We observed that the triplications arose through different mechanisms in the patients: it was de novo in one patient, inherited from a triplication carrier in two cases, while the father of the twins is a 1q21.1 duplication carrier. The de novo triplication contained copies of both maternal alleles, suggesting it was generated by a combination of inter- and intrachromosomal recombination.

PMID: 26327614 [PubMed - indexed for MEDLINE]

Drosophila mutants of the autism candidate gene neurobeachin (rugose) exhibit neuro-developmental disorders, aberrant synaptic properties, altered locomotion, and impaired adult social behavior and activity patterns.

August 20, 2016 - 8:55am
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Drosophila mutants of the autism candidate gene neurobeachin (rugose) exhibit neuro-developmental disorders, aberrant synaptic properties, altered locomotion, and impaired adult social behavior and activity patterns.

J Neurogenet. 2015;29(2-3):135-43

Authors: Wise A, Tenezaca L, Fernandez RW, Schatoff E, Flores J, Ueda A, Zhong X, Wu CF, Simon AF, Venkatesh T

Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder in humans characterized by complex behavioral deficits, including intellectual disability, impaired social interactions, and hyperactivity. ASD exhibits a strong genetic component with underlying multigene interactions. Candidate gene studies have shown that the neurobeachin (NBEA) gene is disrupted in human patients with idiopathic autism ( Castermans et al., 2003 ). The NBEA gene spans the common fragile site FRA 13A and encodes a signal scaffold protein ( Savelyeva et al., 2006 ). In mice, NBEA has been shown to be involved in the trafficking and function of a specific subset of synaptic vesicles. ( Medrihan et al., 2009 ; Savelyeva et al., 2006 ). Rugose (rg) is the Drosophila homolog of the mammalian and human NBEA. Our previous genetic and molecular analyses have shown that rg encodes an A kinase anchor protein (DAKAP 550), which interacts with components of the epidermal growth factor receptor or EGFR and Notch-mediated signaling pathways, facilitating cross talk between these and other pathways ( Shamloula et al., 2002 ). We now present functional data from studies on the larval neuromuscular junction that reveal abnormal synaptic architecture and physiology. In addition, adult rg loss-of-function mutants exhibit defective social interactions, impaired habituation, aberrant locomotion, and hyperactivity. These results demonstrate that Drosophila NBEA (rg) mutants exhibit phenotypic characteristics reminiscent of human ASD and thus could serve as a genetic model for studying ASDs.

PMID: 26100104 [PubMed - indexed for MEDLINE]

Using endophenotypes to examine molecules related to candidate genes as novel therapeutics: The "endophenotype-associated surrogate endpoint (EASE)" concept.

August 20, 2016 - 8:55am
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Using endophenotypes to examine molecules related to candidate genes as novel therapeutics: The "endophenotype-associated surrogate endpoint (EASE)" concept.

Neurosci Res. 2015 Oct;99:1-7

Authors: Yamasue H

Abstract
In this article, a new concept of an "endophenotype-associated surrogate endpoint (EASE)" is proposed. To examine effect of a novel therapeutic molecule on a target phenotype of a genotype associated with the molecule, state-dependent aspect of an endophenotype can be used as a surrogate endpoint. Desired characteristics for EASE are (1) a close relationship to the endophenotype associated with therapeutics, (2) longitudinal changes in illness severity, while the original "endophenotype" is primarily state independent, (3) a physical sign or laboratory measurement that occurs in association with a pathological process and has putative diagnostic and/or prognostic utility, and (4) serves as a substitute for a clinically meaningful endpoint. Advantages are expected for both surrogate endpoints in drug development and endophenotypes in uncovering pathogenesis. EASE are closer to molecules than clinically meaningful endpoints and can respond to administration of the molecule in a more direct manner. Therefore, a statistically significant effect is likely to be observed in clinical trials with smaller sample sizes and shorter durations. As with endophenotypes, reduced heterogeneity might be expected especially in heterogeneous syndromes such as psychiatric disorders. Potential interactions (e.g., elucidating biological mechanisms underlying novel treatments) can be further expected.

PMID: 26055442 [PubMed - indexed for MEDLINE]

AUTS2 Syndrome in a 68-year-old female: Natural history and further delineation of the phenotype.

August 18, 2016 - 8:49am

AUTS2 Syndrome in a 68-year-old female: Natural history and further delineation of the phenotype.

Am J Med Genet A. 2016 Aug 17;

Authors: Sengun E, Yararbas K, Kasakyan S, Alanay Y

Abstract
Here we summarize the clinical and molecular findings in a 68-year-old female with dysmorphic features, mild-to-moderate intellectual disability, and behavioral findings suggesting autism spectrum disorder. SNP array analysis demonstrated a 257 kb deletion comprising exon 6 of AUTS2. This clinical report provides the natural history in the eldest patient yet to be reported, and complements the existing evidence suggesting that disruption of the AUTS2 leads to a recently delineated neurodevelopmental phenotype with a wide spectrum, namely "AUTS2 Syndrome." © 2016 Wiley Periodicals, Inc.

PMID: 27531620 [PubMed - as supplied by publisher]

Genetic Epidemiology of Mitochondrial Pathogenic Variants Causing Nonsyndromic Hearing Loss in a Large Cohort of South Indian Hearing Impaired Individuals.

August 18, 2016 - 8:49am

Genetic Epidemiology of Mitochondrial Pathogenic Variants Causing Nonsyndromic Hearing Loss in a Large Cohort of South Indian Hearing Impaired Individuals.

Ann Hum Genet. 2016 Sep;80(5):257-73

Authors: Subathra M, Ramesh A, Selvakumari M, Karthikeyen NP, Srisailapathy CR

Abstract
Mitochondria play a critical role in the generation of metabolic energy in the form of ATP. Tissues and organs that are highly dependent on aerobic metabolism are involved in mitochondrial disorders including nonsyndromic hearing loss (NSHL). Seven pathogenic variants leading to NSHL have so far been reported on two mitochondrial genes: MT-RNR1 encoding 12SrRNA and MT-TS1 encoding tRNA for Ser((UCN)) . We screened 729 prelingual NSHL subjects to determine the prevalence of MT-RNR1 variants at position m.961, m.1555A>G and m.1494C>T, and MT-TS1 m.7445A>G, m.7472insC m.7510T>C and m.7511T>C variants. Mitochondrial pathogenic variants were found in eight probands (1.1%). Five of them were found to have the m.1555A>G variant, two others had m.7472insC and one proband had m.7444G>A. The extended relatives of these probands showed variable degrees of hearing loss and age at onset. This study shows that mitochondrial pathogenic alleles contribute to about 1% prelingual hearing loss. This study will henceforth provide the reference for the prevalence of mitochondrial pathogenic alleles in the South Indian population, which to date has not been estimated. The m.1555A>G variant is a primary predisposing genetic factor for the development of hearing loss. Our study strongly suggests that mitochondrial genotyping should be considered for all hearing impaired individuals and particularly in families where transmission is compatible with maternal inheritance, after ruling out the most common variants.

PMID: 27530448 [PubMed - in process]

Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization.

August 18, 2016 - 8:49am
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Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization.

Biol Chem. 2015 Nov;396(11):1233-40

Authors: Ciccoli L, De Felice C, Leoncini S, Signorini C, Cortelazzo A, Zollo G, Pecorelli A, Rossi M, Hayek J

Abstract
In this review, we summarize the current evidence on the erythrocyte as a previously unrecognized target cell in Rett syndrome, a rare (1:10 000 females) and devastating neurodevelopmental disorder caused by loss-of-function mutations in a single gene (i.e. MeCP2, CDKL5, or rarely FOXG1). In particular, we focus on morphological changes, membrane oxidative damage, altered membrane fatty acid profile, and aberrant skeletal organization in erythrocytes from patients with typical Rett syndrome and MeCP2 gene mutations. The beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) are also summarized for this condition to be considered as a 'model' condition for autism spectrum disorders.

PMID: 26040005 [PubMed - indexed for MEDLINE]

Infantile spasms and 15q11.2q13.1 chromosome duplication in two successive generations.

August 17, 2016 - 2:46pm
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Infantile spasms and 15q11.2q13.1 chromosome duplication in two successive generations.

Eur J Paediatr Neurol. 2016 Jan;20(1):164-7

Authors: Riikonen RS, Wallden T, Kokkonen H

Abstract
Familial cases of West syndrome have been reported only in Japan. In that study no chromosomal analyses were made. It has been suggested that microarray analysis should be included in the diagnostic evaluation of patients with infantile spasms and developmental delay, when an evaluation for structural brain lesions and metabolic disorders reveal no abnormal findings. We report here the first case of infantile spasms and 15q11.2q13.1 chromosome duplication in two successive generations. The daughter and mother with infantile spasms, and the autistic son had the duplication. The clinical course of infantile spasms was very similar in the mother and daughter. The spasms were primarily considered to be of unknown aetiology. Chromosomal microarray analysis revealed a 6.2 Mb size 15q11.2q13.1 duplication. The duplication belongs to the 15q11q13 duplication syndrome (OMIM 608636) which when maternally derived is characterised by neuro-behavioural disorders like autism, hypotonia, cognitive deficit, language delay and epilepsy. The proportion of patients with unknown aetiology for infantile spasms will decrease when more careful chromosomal studies are made. Our report expands the phenotype of chromosome 15q duplication syndrome and is the first report of this abnormality in two successive generations of infantile spasms.

PMID: 26685108 [PubMed - indexed for MEDLINE]

Chromosome 17q21.31 duplication syndrome: Description of a new familiar case and further delineation of the clinical spectrum.

August 17, 2016 - 2:46pm
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Chromosome 17q21.31 duplication syndrome: Description of a new familiar case and further delineation of the clinical spectrum.

Eur J Paediatr Neurol. 2016 Jan;20(1):183-7

Authors: Natacci F, Alfei E, Tararà L, D'Arrigo S, Zuffardi O, Gentilin B, Pantaleoni C

Abstract
INTRODUCTION: 17q21.31 microduplication syndrome is a recently described condition associated with a broad clinical spectrum, of which psychomotor delay, behavioral disorders and poor social interaction seem to be the most consistent features. Only seven patients have been reported thus far. All have behavioral disorders reminiscent of the autistic spectrum with intellectual skills ranging from normal to mild intellectual deficiency. Other features are variable with no striking common phenotypic features.
CASE STUDY: Here we describe the segregation of 17q21.31 duplication in an Italian family.
DISCUSSION: Clinical features and genetic data are reported, and compared with previously reported patients with 17q21.31 microduplication. A comparison of clinical manifestations between deletion and duplication syndromes of the chromosome regione is provided.

PMID: 26565673 [PubMed - indexed for MEDLINE]

Molecular mechanisms underlying neurodevelopmental disorders, ADHD and autism.

August 16, 2016 - 8:43am
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Molecular mechanisms underlying neurodevelopmental disorders, ADHD and autism.

Rom J Morphol Embryol. 2016;57(2):361-6

Authors: Bădescu GM, Fîlfan M, Sandu RE, Surugiu R, Ciobanu O, Popa-Wagner A

Abstract
Neurodevelopmental disorders such as attention deficit hyperactivity disorder and autism represent a significant economic burden, which justify vigorous research to uncover its genetics and developmental clinics for a diagnostic workup. The urgency of addressing attention deficit hyperactivity disorder comorbidities is seen in the chilling fact that attention deficit hyperactivity disorder (ADHD), mood disorders, substance use disorders and obesity each increase the risk for mortality. However, data about comorbidity is mainly descriptive, with mechanistic studies limited to genetic epidemiological studies that document shared genetic risk factors among these conditions. Autism and intellectual disability affects 1.5 to 2% of the population in Western countries with many individuals displaying social-emotional agnosia and having difficulty in forming attachments and relationships. Underlying mechanisms include: (i) dysfunctions of neuronal miRNAs; (ii) deletions in the chromosome 21, subtelomeric deletions, duplications and a maternally inherited duplication of the chromosomal region 15q11-q13; (iii) microdeletions in on the long (q) arm of the chromosome in a region designated q21.1 increases the risk of delayed development, intellectual disability, physical abnormalities, and neurological and psychiatric problems associated with autism, schizophrenia, and epilepsy and weak muscle tone (hypotonia); (iv) interstitial duplications encompassing 16p13.11.

PMID: 27516006 [PubMed - in process]

The importance of de novo mutations for pediatric neurological disease--It is not all in utero or birth trauma.

August 16, 2016 - 8:43am
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The importance of de novo mutations for pediatric neurological disease--It is not all in utero or birth trauma.

Mutat Res Rev Mutat Res. 2016 Jan-Mar;767:42-58

Authors: Erickson RP

Abstract
The advent of next generation sequencing (NGS, which consists of massively parallel sequencing to perform TGS (total genome sequencing) or WES (whole exome sequencing)) has abundantly discovered many causative mutations in patients with pediatric neurological disease. A surprisingly high number of these are de novo mutations which have not been inherited from either parent. For epilepsy, autism spectrum disorders, and neuromotor disorders, including cerebral palsy, initial estimates put the frequency of causative de novo mutations at about 15% and about 10% of these are somatic. There are some shared mutated genes between these three classes of disease. Studies of copy number variation by comparative genomic hybridization (CGH) proceded the NGS approaches but they also detect de novo variation which is especially important for ASDs. There are interesting differences between the mutated genes detected by CGS and NGS. In summary, de novo mutations cause a very significant proportion of pediatric neurological disease.

PMID: 27036065 [PubMed - indexed for MEDLINE]

The Idea Is Good, but…: Failure to Replicate Associations of Oxytocinergic Polymorphisms with Face-Inversion in the N170.

August 16, 2016 - 8:43am
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The Idea Is Good, but…: Failure to Replicate Associations of Oxytocinergic Polymorphisms with Face-Inversion in the N170.

PLoS One. 2016;11(3):e0151991

Authors: Munk AJ, Hermann A, El Shazly J, Grant P, Hennig J

Abstract
BACKGROUND: In event-related potentials, the N170 manifests itself especially in reaction to faces. In the healthy population, face-inversion leads to stronger negative amplitudes and prolonged latencies of the N170, effects not being present in patients with autism-spectrum-disorder (ASD). ASD has frequently been associated with differences in oxytocinergic neurotransmission. This ERP-study aimed to investigate the face-inversion effect in association with oxytocinergic candidate genes. It was expected that risk-allele-carriers of the oxytocin-receptor-gene-polymorphism (rs53576) and of CD38 (rs379863) responded similar to upright and inverted faces as persons with ASD. Additionally, reactions to different facial emotional expressions were studied. As there have been difficulties with replications of those molecular genetic association studies, we aimed to replicate our findings in a second study.
METHOD: Seventy-two male subjects in the first-, and seventy-eight young male subjects in the replication-study conducted a face-inversion-paradigm, while recording EEG. DNA was extracted from buccal cells.
RESULTS: Results revealed stronger N170-amplitudes and longer latencies in reaction to inverted faces in comparison to upright ones. Furthermore, effects of emotion on N170 were evident. Those effects were present in the first and in the second study. Whereas we found molecular-genetic associations of oxytocinergic polymorphisms with the N170 in the first study, we failed to do so in the replication sample.
CONCLUSION: Results indicate that a deeper theoretical understanding of this research-field is needed, in order to generate possible explanations for these findings. Results, furthermore, support the hypotheses that success of reproducibility is correlated with strength of lower original p-values and larger effect sizes in the original study.

PMID: 27015428 [PubMed - indexed for MEDLINE]

Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors.

August 16, 2016 - 8:43am
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Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors.

Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):E1575-84

Authors: Li W, Xu X, Pozzo-Miller L

Abstract
Deficits in long-term potentiation (LTP) at central excitatory synapses are thought to contribute to cognitive impairments in neurodevelopmental disorders associated with intellectual disability and autism. Using the methyl-CpG-binding protein 2 (Mecp2) knockout (KO) mouse model of Rett syndrome, we show that naïve excitatory synapses onto hippocampal pyramidal neurons of symptomatic mice have all of the hallmarks of potentiated synapses. Stronger Mecp2 KO synapses failed to undergo LTP after either theta-burst afferent stimulation or pairing afferent stimulation with postsynaptic depolarization. On the other hand, basal synaptic strength and LTP were not affected in slices from younger presymptomatic Mecp2 KO mice. Furthermore, spine synapses in pyramidal neurons from symptomatic Mecp2 KO are larger and do not grow in size or incorporate GluA1 subunits after electrical or chemical LTP. Our data suggest that LTP is occluded in Mecp2 KO mice by already potentiated synapses. The higher surface levels of GluA1-containing receptors are consistent with altered expression levels of proteins involved in AMPA receptor trafficking, suggesting previously unidentified targets for therapeutic intervention for Rett syndrome and other MECP2-related disorders.

PMID: 26929363 [PubMed - indexed for MEDLINE]

An expanded sequence context model broadly explains variability in polymorphism levels across the human genome.

August 16, 2016 - 8:43am
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An expanded sequence context model broadly explains variability in polymorphism levels across the human genome.

Nat Genet. 2016 Apr;48(4):349-55

Authors: Aggarwala V, Voight BF

Abstract
The rate of single-nucleotide polymorphism varies substantially across the human genome and fundamentally influences evolution and incidence of genetic disease. Previous studies have only considered the immediately flanking nucleotides around a polymorphic site--the site's trinucleotide sequence context--to study polymorphism levels across the genome. Moreover, the impact of larger sequence contexts has not been fully clarified, even though context substantially influences rates of polymorphism. Using a new statistical framework and data from the 1000 Genomes Project, we demonstrate that a heptanucleotide context explains >81% of variability in substitution probabilities, highlighting new mutation-promoting motifs at ApT dinucleotide, CAAT and TACG sequences. Our approach also identifies previously undocumented variability in C-to-T substitutions at CpG sites, which is not immediately explained by differential methylation intensity. Using our model, we present informative substitution intolerance scores for genes and a new intolerance score for amino acids, and we demonstrate clinical use of the model in neuropsychiatric diseases.

PMID: 26878723 [PubMed - indexed for MEDLINE]

Shank3 is localized in axons and presynaptic specializations of developing hippocampal neurons and involved in the modulation of NMDA receptor levels at axon terminals.

August 16, 2016 - 8:43am
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Shank3 is localized in axons and presynaptic specializations of developing hippocampal neurons and involved in the modulation of NMDA receptor levels at axon terminals.

J Neurochem. 2016 Apr;137(1):26-32

Authors: Halbedl S, Schoen M, Feiler MS, Boeckers TM, Schmeisser MJ

Abstract
Autism-related Shank1, Shank2, and Shank3 are major postsynaptic scaffold proteins of excitatory glutamatergic synapses. A few studies, however, have already indicated that within a neuron, the presence of Shank family members is not limited to the postsynaptic density. By separating axons from dendrites of developing hippocampal neurons in microfluidic chambers, we show that RNA of all three Shank family members is present within axons. Immunostaining confirms these findings as all three Shanks are indeed found within separated axons and further co-localize with well-known proteins of the presynaptic specialization in axon terminals. Therefore, Shank proteins might not only serve as postsynaptic scaffold proteins, but also play a crucial role during axonal outgrowth and presynaptic development and function. This is supported by our findings that shRNA-mediated knockdown of Shank3 results in up-regulation of the NMDA receptor subunit GluN1 in axon terminals. Taken together, our findings will have major implications for the future analysis of neuronal Shank biology in both health and disease. Shank1, Shank2, and Shank3 are major postsynaptic scaffold proteins of excitatory glutamatergic synapses strongly related to several neuropsychiatric disorders. However, a few studies have already implicated a functional role of the Shanks beyond the postsynaptic density (PSD). We here show that all three Shanks are localized in both axons and pre-synaptic specializiations of developing hippocampal neurons in culture. We further provide evidence that Shank3 is involved in the modulation of NMDA receptor levels at axon terminals. Taken together, our study will open up novel avenues for the future analysis of neuronal Shank biology in both health and disease.

PMID: 26725465 [PubMed - indexed for MEDLINE]

[Oxytocin in the treatment of the social deficits associated to autism spectrum disorders].

August 16, 2016 - 8:43am
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[Oxytocin in the treatment of the social deficits associated to autism spectrum disorders].

Rev Neurol. 2015 Nov 1;61(9):421-8

Authors: Cachafeiro-Espino C, Vale-Martínez AM

Abstract
INTRODUCTION: The recent involvement of oxytocin in social behavior of animals and humans has motivated the study of its effects on the social behavior of individuals with autism spectrum disorders (ASD).
AIMS: To review the current state of oxytocin studies concerning its therapeutic potential in treating social deficits of the ASD population, and to establish likely future directions to be taken by the studies in this field.
DEVELOPMENT: Some studies have linked oxytocin to the pathophysiology of autistic disorders. Most studies that have administered oxytocin (mainly with intranasal administration of 24 IU) to ASD subjects have shown significant improvements in their social performance with acceptable safety parameters. However, there is controversial data as the outcome measures are widely dispersed, the samples are reduced and heterogeneous, and the treatment durations are different. The limitations related to the lack of understanding of the oxytocin's action mechanisms and the symptomatic heterogeneity of ASD are hampering progress towards the establishment of oxytocin as a treatment of ASD patients. Recent studies suggest the investigation of the combination of the oxytocin treatment with social skills training, and the enhancement of endogenous secretion of oxytocin.
CONCLUSION: The effects of oxytocin are promising regarding the treatment of social deficits in ASD individuals. Future studies should aim to facilitate understanding of the oxytocin's ways of action and to establish the optimal treatment regime.

PMID: 26503318 [PubMed - indexed for MEDLINE]

A truncating mutation in Alzheimer's disease inactivates neuroligin-1 synaptic function.

August 16, 2016 - 8:43am
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A truncating mutation in Alzheimer's disease inactivates neuroligin-1 synaptic function.

Neurobiol Aging. 2015 Dec;36(12):3171-5

Authors: Tristán-Clavijo E, Camacho-Garcia RJ, Robles-Lanuza E, Ruiz A, van der Zee J, Van Broeckhoven C, Hernandez I, Martinez-Mir A, Scholl FG

Abstract
Neuroligins (NLs) are cell-adhesion proteins that regulate synapse formation and function. Neuroligin 1 (NL1) promotes the formation of glutamatergic synapses and mediates long-term potentiation in mouse models. Thus, altered NL1 function could mediate the synaptic and memory deficits associated with Alzheimer's disease (AD). Here, we describe a frameshift mutation, c.875_876insTT, in the neuroligin 1 gene (NLGN1) in a patient with AD and familial history of AD. The insertion generates a premature stop codon in the extracellular domain of NL1 (p.Thr271fs). Expression of mutant NL1 shows accumulation of truncated NL1 proteins in the endoplasmic reticulum. In hippocampal neurons, the p.Thr271fs mutation abolishes the ability of NL1 to promote the formation of glutamatergic synapses. Our data support a role for inactivating mutations in NLGN1 in AD. Previous studies have reported rare mutations in X-linked NLGNL3 and NLGNL4 genes in patients with autism, which result in the inactivation of the mutant alleles. Therefore, together with a role in neurodevelopmental disorders, altered NL function could underlie the molecular mechanisms associated with brain diseases in the elderly.

PMID: 26440732 [PubMed - indexed for MEDLINE]

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