pubmed: autism and genetics

Subscribe to pubmed: autism and genetics feed pubmed: autism and genetics
NCBI: db=pubmed; Term=autism AND genetics
Updated: 53 min 44 sec ago

Relationship between ST8SIA2, polysialic acid and its binding molecules, and psychiatric disorders.

September 8, 2016 - 7:17am
Related Articles

Relationship between ST8SIA2, polysialic acid and its binding molecules, and psychiatric disorders.

Biochim Biophys Acta. 2016 Aug;1860(8):1739-52

Authors: Sato C, Hane M, Kitajima K

Abstract
Polysialic acid (polySia, PSA) is a unique and functionally important glycan, particularly in vertebrate brains. It is involved in higher brain functions such as learning, memory, and social behaviors. Recently, an association between several genetic variations and single nucleotide polymorphisms (SNPs) of ST8SIA2/STX, one of two polysialyltransferase genes in vertebrates, and psychiatric disorders, such as schizophrenia (SZ), bipolar disorder (BD), and autism spectrum disorder (ASD), was reported based on candidate gene approaches and genome-wide studies among normal and mental disorder patients. It is of critical importance to determine if the reported mutations and SNPs in ST8SIA2 lead to impairments of the structure and function of polySia, which is the final product of ST8SIA2. To date, however, only a few such forward-directed studies have been conducted. In addition, the molecular mechanisms underlying polySia-involved brain functions remain unknown, although polySia was shown to have an anti-adhesive effect. In this report, we review the relationships between psychiatric disorders and polySia and/or ST8SIA2, and describe a new function of polySia as a regulator of neurologically active molecules, such as brain-derived neurotrophic factor (BDNF) and dopamine, which are deeply involved in psychiatric disorders. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.

PMID: 27105834 [PubMed - indexed for MEDLINE]

Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism.

September 8, 2016 - 7:17am
Related Articles

Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism.

Sci Rep. 2015;5:16239

Authors: Maekawa M, Iwayama Y, Ohnishi T, Toyoshima M, Shimamoto C, Hisano Y, Toyota T, Balan S, Matsuzaki H, Iwata Y, Takagai S, Yamada K, Ota M, Fukuchi S, Okada Y, Akamatsu W, Tsujii M, Kojima N, Owada Y, Okano H, Mori N, Yoshikawa T

Abstract
The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology.

PMID: 26548558 [PubMed - indexed for MEDLINE]

Genetic Variants of Angiotensin-Converting Enzyme Are Linked to Autism: A Case-Control Study.

September 7, 2016 - 7:13am
Related Articles

Genetic Variants of Angiotensin-Converting Enzyme Are Linked to Autism: A Case-Control Study.

PLoS One. 2016;11(4):e0153667

Authors: Firouzabadi N, Ghazanfari N, Alavi Shoushtari A, Erfani N, Fathi F, Bazrafkan M, Bahramali E

Abstract
BACKGROUND: Autism is a disease of complex nature with a significant genetic component. The importance of renin-angiotensin system (RAS) elements in cognition and behavior besides the interaction of angiotensin II (Ang II), the main product of angiotensin-converting enzyme (ACE), with neurotransmitters in CNS, especially dopamine, proposes the involvement of RAS in autism. Since the genetic architecture of autism has remained elusive, here we postulated that genetic variations in RAS are associated with autism.
METHODS: Considering the relation between the three polymorphisms of ACE (I/D, rs4343 and rs4291) with the level of ACE activity, we have investigated this association with autism, in a case-control study. Genotype and allele frequencies of polymorphisms were determined in DNAs extracted from venous blood of 120 autistic patients and their age and sex-matched healthy controls, using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods.
RESULTS: There were strong associations between both DD genotype of ACE I/D and the D allele, with autism (P = 0.006, OR = 2.9, 95% CI = 1.64-5.13 and P = 0.006, OR = 2.18, 95% CI = 1.37-3.48 respectively). Furthermore, a significant association between the G allele of rs4343 and autism was observed (P = 0.006, OR = 1.84, 95%CI = 1.26-2.67). Moreover, haplotype analysis revealed an association between DTG haplotype and autism (P = 0.008).
CONCLUSION: Our data suggests the involvement of RAS genetic diversity in increasing the risk of autism.

PMID: 27082637 [PubMed - indexed for MEDLINE]

Subthreshold traits of the broad autistic spectrum are distributed across different subgroups in parents, but not siblings, of probands with autism.

September 7, 2016 - 7:13am
Related Articles

Subthreshold traits of the broad autistic spectrum are distributed across different subgroups in parents, but not siblings, of probands with autism.

Eur Child Adolesc Psychiatry. 2014 Apr;23(4):225-33

Authors: Robel L, Rousselot-Pailley B, Fortin C, Levy-Rueff M, Golse B, Falissard B

Abstract
Autism is a categorical developmental disorder characterized by impairment in socialization, communication, and by restricted and circumscribed interests. Several authors have described the presence of subthreshold autistic traits in the general population, pervasive developmental disorders representing the extreme end of their distribution. In this study, we explored the presence of autistic traits in siblings and parents of a proband with autism, and in siblings and parents of a normally developing child, using the previously validated self-report French Autism Quotient, an adaptation of the AQ developed by S. Baron-Cohen. Scores were distributed between two main factors, F1 corresponding to socialization and communication, F2 to imagination and rigidity. Here, we show that both parents and siblings of a child with autism have more symptomatic scores in the domains of communication and socialization. In addition, we show that in these families the parents, but not the siblings, are distributed across different subcategories, according to their scores for the F1 and F2 domains. We hypothesize that these different subgroups may correspond to different underlying genetic mechanisms.

PMID: 23864543 [PubMed - indexed for MEDLINE]

Novel mechanisms and treatment approaches in autism spectrum disorder.

September 2, 2016 - 7:02am

Novel mechanisms and treatment approaches in autism spectrum disorder.

Discov Med. 2016 Aug;22(119):47-54

Authors: Brian J, Doyle-Thomas K, Baribeau D, Anagnostou E

Abstract
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by marked heterogeneity in biology, expression, and response to treatment. The past decade has yielded considerable progress in understanding the underlying biological mechanisms, in characterizing the earliest behavioral phenotype(s), and in developing and evaluating effective treatments for ASD. This review highlights recent research advances in genetics and neuroimaging, as well as in novel behavioral and psychopharmacological treatment approaches, arguing for the value of trans-disciplinary initiatives to move the field forward exponentially. Despite considerable complexity, patterns are beginning to emerge that can inform the identification of novel treatment targets and approaches. The next generation of major innovations in ASD research will involve collaborations across genetics/genomics, neuroimaging, and intervention science. Such efforts, currently under way, hold tremendous promise for exponentially increasing our capacity to understand the mechanisms that contribute to the emergence of ASD and to develop and evaluate personalized interventions that yield maximal impact in a meaningful way.

PMID: 27585230 [PubMed - as supplied by publisher]

Severity of ASD symptoms and their correlation with the presence of copy number variations and exposure to first trimester ultrasound.

September 2, 2016 - 7:02am

Severity of ASD symptoms and their correlation with the presence of copy number variations and exposure to first trimester ultrasound.

Autism Res. 2016 Sep 1;

Authors: Jane Webb S, Garrison MM, Bernier R, McClintic AM, King BH, Mourad PD

Abstract
Current research suggests that incidence and heterogeneity of autism spectrum disorder (ASD) symptoms may arise through a variety of exogenous and/or endogenous factors. While subject to routine clinical practice and generally considered safe, there exists speculation, though no human data, that diagnostic ultrasound may also contribute to ASD severity, supported by experimental evidence that exposure to ultrasound early in gestation could perturb brain development and alter behavior. Here we explored a modified triple hit hypothesis [Williams & Casanova, ] to assay for a possible relationship between the severity of ASD symptoms and (1) ultrasound exposure (2) during the first trimester of pregnancy in fetuses with a (3) genetic predisposition to ASD. We did so using retrospective analysis of data from the SSC (Simon's Simplex Collection) autism genetic repository funded by the Simons Foundation Autism Research Initiative. We found that male children with ASD, copy number variations (CNVs), and exposure to first trimester ultrasound had significantly decreased non-verbal IQ and increased repetitive behaviors relative to male children with ASD, with CNVs, and no ultrasound. These data suggest that heterogeneity in ASD symptoms may result, at least in part, from exposure to diagnostic ultrasound during early prenatal development of children with specific genetic vulnerabilities. These results also add weight to on-going concerns expressed by the FDA about non-medical use of diagnostic ultrasound during pregnancy. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 27582229 [PubMed - as supplied by publisher]

Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength.

September 2, 2016 - 7:02am

Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength.

J Neurosci. 2016 Aug 31;36(35):9124-34

Authors: Arons MH, Lee K, Thynne CJ, Kim SA, Schob C, Kindler S, Montgomery JM, Garner CC

Abstract
UNLABELLED: Shank3 is a multidomain scaffold protein localized to the postsynaptic density of excitatory synapses. Functional studies in vivo and in vitro support the concept that Shank3 is critical for synaptic plasticity and the trans-synaptic coupling between the reliability of presynaptic neurotransmitter release and postsynaptic responsiveness. However, how Shank3 regulates synaptic strength remains unclear. The C terminus of Shank3 contains a sterile alpha motif (SAM) domain that is essential for its postsynaptic localization and also binds zinc, thus raising the possibility that changing zinc levels modulate Shank3 function in dendritic spines. In support of this hypothesis, we find that zinc is a potent regulator of Shank3 activation and dynamics in rat hippocampal neurons. Moreover, we show that zinc modulation of synaptic transmission is Shank3 dependent. Interestingly, an autism spectrum disorder (ASD)-associated variant of Shank3 (Shank3(R87C)) retains its zinc sensitivity and supports zinc-dependent activation of AMPAR-mediated synaptic transmission. However, elevated zinc was unable to rescue defects in trans-synaptic signaling caused by the R87C mutation, implying that trans-synaptic increases in neurotransmitter release are not necessary for the postsynaptic effects of zinc. Together, these data suggest that Shank3 is a key component of a zinc-sensitive signaling system, regulating synaptic strength that may be impaired in ASD.
SIGNIFICANCE STATEMENT: Shank3 is a postsynaptic protein associated with neurodevelopmental disorders such as autism and schizophrenia. In this study, we show that Shank3 is a key component of a zinc-sensitive signaling system that regulates excitatory synaptic transmission. Intriguingly, an autism-associated mutation in Shank3 partially impairs this signaling system. Therefore, perturbation of zinc homeostasis may impair, not only synaptic functionality and plasticity, but also may lead to cognitive and behavioral abnormalities seen in patients with psychiatric disorders.

PMID: 27581454 [PubMed - in process]

Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling.

September 2, 2016 - 7:02am
Related Articles

Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling.

PLoS One. 2016;11(4):e0153329

Authors: Wen Y, Alshikho MJ, Herbert MR

Abstract
We used established databases in standard ways to systematically characterize gene ontologies, pathways and functional linkages in the large set of genes now associated with autism spectrum disorders (ASDs). These conditions are particularly challenging--they lack clear pathognomonic biological markers, they involve great heterogeneity across multiple levels (genes, systemic biological and brain characteristics, and nuances of behavioral manifestations)-and yet everyone with this diagnosis meets the same defining behavioral criteria. Using the human gene list from Simons Foundation Autism Research Initiative (SFARI) we performed gene set enrichment analysis with the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database, and then derived a pathway network from pathway-pathway functional interactions again in reference to KEGG. Through identifying the GO (Gene Ontology) groups in which SFARI genes were enriched, mapping the coherence between pathways and GO groups, and ranking the relative strengths of representation of pathway network components, we 1) identified 10 disease-associated and 30 function-associated pathways 2) revealed calcium signaling pathway and neuroactive ligand-receptor interaction as the most enriched, statistically significant pathways from the enrichment analysis, 3) showed calcium signaling pathways and MAPK signaling pathway to be interactive hubs with other pathways and also to be involved with pervasively present biological processes, 4) found convergent indications that the process "calcium-PRC (protein kinase C)-Ras-Raf-MAPK/ERK" is likely a major contributor to ASD pathophysiology, and 5) noted that perturbations associated with KEGG's category of environmental information processing were common. These findings support the idea that ASD-associated genes may contribute not only to core features of ASD themselves but also to vulnerability to other chronic and systemic problems potentially including cancer, metabolic conditions and heart diseases. ASDs may thus arise, or emerge, from underlying vulnerabilities related to pleiotropic genes associated with pervasively important molecular mechanisms, vulnerability to environmental input and multiple systemic co-morbidities.

PMID: 27055244 [PubMed - indexed for MEDLINE]

Heterozygous deletion of α-neurexin I or α-neurexin II results in behaviors relevant to autism and schizophrenia.

September 2, 2016 - 7:02am
Related Articles

Heterozygous deletion of α-neurexin I or α-neurexin II results in behaviors relevant to autism and schizophrenia.

Behav Neurosci. 2015 Dec;129(6):765-76

Authors: Dachtler J, Ivorra JL, Rowland TE, Lever C, Rodgers RJ, Clapcote SJ

Abstract
The neurexins are a family of presynaptic cell adhesion molecules. Human genetic studies have found heterozygous deletions affecting NRXN1 and NRXN2, encoding α-neurexin I (Nrxn1α) and α-neurexin II (Nrxn2α), in individuals with autism spectrum disorders and schizophrenia. However, the link between α-neurexin deficiency and the manifestation of psychiatric disorders remain unclear. To assess whether the heterozygous loss of neurexins results in behaviors relevant to autism or schizophrenia, we used mice with heterozygous (HET) deletion of Nrxn1α or Nrxn2α. We found that in a test of social approach, Nrxn1α HET mice show no social memory for familiar versus novel conspecifics. In a passive avoidance test, female Nrxn1α HET mice cross to the conditioned chamber sooner than female wild-type and Nrxn2α HET mice. Nrxn2α HET mice also express a lack of long-term object discrimination, indicating a deficit in cognition. The observed Nrxn1α and Nrxn2α genotypic effects were specific, as neither HET deletion had effects on a wide range of other behavioral measures, including several measures of anxiety. Our findings demonstrate that the heterozygous loss of α-neurexin I and α-neurexin II in mice leads to phenotypes relevant to autism and schizophrenia.

PMID: 26595880 [PubMed - indexed for MEDLINE]

Auditory processing and morphological anomalies in medial geniculate nucleus of Cntnap2 mutant mice.

September 2, 2016 - 7:02am
Related Articles

Auditory processing and morphological anomalies in medial geniculate nucleus of Cntnap2 mutant mice.

Behav Neurosci. 2015 Dec;129(6):731-43

Authors: Truong DT, Rendall AR, Castelluccio BC, Eigsti IM, Fitch RH

Abstract
Genetic epidemiological studies support a role for CNTNAP2 in developmental language disorders such as autism spectrum disorder, specific language impairment, and dyslexia. Atypical language development and function represent a core symptom of autism spectrum disorder (ASD), with evidence suggesting that aberrant auditory processing-including impaired spectrotemporal processing and enhanced pitch perception-may both contribute to an anomalous language phenotype. Investigation of gene-brain-behavior relationships in social and repetitive ASD symptomatology have benefited from experimentation on the Cntnap2 knockout (KO) mouse. However, auditory-processing behavior and effects on neural structures within the central auditory pathway have not been assessed in this model. Thus, this study examined whether auditory-processing abnormalities were associated with mutation of the Cntnap2 gene in mice. Cntnap2 KO mice were assessed on auditory-processing tasks including silent gap detection, embedded tone detection, and pitch discrimination. Cntnap2 knockout mice showed deficits in silent gap detection but a surprising superiority in pitch-related discrimination as compared with controls. Stereological analysis revealed a reduction in the number and density of neurons, as well as a shift in neuronal size distribution toward smaller neurons, in the medial geniculate nucleus of mutant mice. These findings are consistent with a central role for CNTNAP2 in the ontogeny and function of neural systems subserving auditory processing and suggest that developmental disruption of these neural systems could contribute to the atypical language phenotype seen in autism spectrum disorder.

PMID: 26501174 [PubMed - indexed for MEDLINE]

Is there an effect of intranasal insulin on development and behaviour in Phelan-McDermid syndrome? A randomized, double-blind, placebo-controlled trial.

September 1, 2016 - 6:58am

Is there an effect of intranasal insulin on development and behaviour in Phelan-McDermid syndrome? A randomized, double-blind, placebo-controlled trial.

Eur J Hum Genet. 2016 Aug 31;

Authors: Zwanenburg RJ, Bocca G, Ruiter SA, Dillingh JH, Flapper BC, van den Heuvel ER, van Ravenswaaij-Arts CM

Abstract
Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is a rare neurodevelopmental disorder with at least 60 children and 35 adults diagnosed in the Netherlands. Clinical features are moderate to severe intellectual disability and behavioural problems in the autism spectrum. Other researchers had observed a beneficial effect of intranasal insulin on development and behaviour in a pilot study in six children with PMS. To validate this effect, we conducted a randomized, double-blind, placebo-controlled clinical trial using a stepped-wedge design. From March 2013 to June 2015, 25 children aged 1-16 years with a molecularly confirmed 22q13.3 deletion including the SHANK3 gene participated in the clinical trial for a period of 18 months. Starting 6 months before the trial, children were systematically assessed for cognitive, language and motor development and for adaptive, social and emotional behaviour every 6 months. The second, third and fourth assessments were followed by daily nose sprays containing either intranasal insulin or intranasal placebo for a 6-month period. A fifth assessment was done directly after the end of the trial. Intranasal insulin did not cause serious adverse events. It increased the level of developmental functioning by 0.4-1.4 months per 6-month period, but the effect was not statistically significant in this small group. We found a stronger effect of intranasal insulin, being significant for cognition and social skills, for children older than 3 years, who usually show a decrease of developmental growth. However, clinical trials in larger study populations are required to prove the therapeutic effect of intranasal insulin in PMS.European Journal of Human Genetics advance online publication, 31 August 2016; doi:10.1038/ejhg.2016.109.

PMID: 27577546 [PubMed - as supplied by publisher]

Functional test of PCDHB11, the most human-specific neuronal surface protein.

September 1, 2016 - 6:58am
Related Articles

Functional test of PCDHB11, the most human-specific neuronal surface protein.

BMC Evol Biol. 2016;16:75

Authors: de Freitas GB, Gonçalves RA, Gralle M

Abstract
BACKGROUND: Brain-expressed proteins that have undergone functional change during human evolution may contribute to human cognitive capacities, and may also leave us vulnerable to specifically human diseases, such as schizophrenia, autism or Alzheimer's disease. In order to search systematically for those proteins that have changed the most during human evolution and that might contribute to brain function and pathology, all proteins with orthologs in chimpanzee, orangutan and rhesus macaque and annotated as being expressed on the surface of cells in the human central nervous system were ordered by the number of human-specific amino acid differences that are fixed in modern populations.
RESULTS: PCDHB11, a beta-protocadherin homologous to murine cell adhesion proteins, stood out with 12 substitutions and maintained its lead after normalizing for protein size and applying weights for amino acid exchange probabilities. Human PCDHB11 was found to cause homophilic cell adhesion, but at lower levels than shown for other clustered protocadherins. Homophilic adhesion caused by a PCDHB11 with reversion of human-specific changes was as low as for modern human PCDHB11; while neither human nor reverted PCDHB11 adhered to controls, they did adhere to each other. A loss of function in PCDHB11 is unlikely because intra-human variability did not increase relative to the other human beta-protocadherins.
CONCLUSIONS: The brain-expressed protein with the highest number of human-specific substitutions is PCDHB11. In spite of its fast evolution and low intra-human variability, cell-based tests on the only proposed function for PCDHB11 did not indicate a functional change.

PMID: 27068704 [PubMed - indexed for MEDLINE]

Association and Promoter Analysis of AVPR1A in Finnish Autism Families.

September 1, 2016 - 6:58am
Related Articles

Association and Promoter Analysis of AVPR1A in Finnish Autism Families.

Autism Res. 2015 Oct;8(5):634-9

Authors: Kantojärvi K, Oikkonen J, Kotala I, Kallela J, Vanhala R, Onkamo P, Järvelä I

Abstract
The arginine vasopressin receptor 1A gene (AVPR1A) is known to affect social communication and has been reported to associate with autism in several studies. Given that the microsatellite RS1 and a few SNPs in the promoter region of the AVPR1A have repeatedly associated with several traits, including autism it is rather surprising that the molecular explanation for these associations has remained unknown, although it has been reported that the allele length of the AVPR1A microsatellites might affect disease risk. Here we carried out an extended association analysis of three microsatellites and 12 tag single nucleotide polymorphisms (SNPs) in and around the AVPR1A gene in 205 Finnish families followed by promoter analysis. FBAT version v2.0.3 was used for family-based genetic association analyses of AVPR1A microsatellites and SNPs. The nearby microsatellite RS1 was found to harbor the best association. Interestingly, there are two potentially relevant transcription factor (TF) binding sites at RS1: for MEF2C and PBX, predicted with the Match algorithm in the TRANSFAC database. Sequence variations changing the affinity of these TFs might partly explain the AVPR1A promoter region associations shown in autism.

PMID: 25707602 [PubMed - indexed for MEDLINE]

Obsessive-Compulsive Disorder in Adults with High-Functioning Autism Spectrum Disorder: What Does Self-Report with the OCI-R Tell Us?

September 1, 2016 - 6:58am
Related Articles

Obsessive-Compulsive Disorder in Adults with High-Functioning Autism Spectrum Disorder: What Does Self-Report with the OCI-R Tell Us?

Autism Res. 2015 Oct;8(5):477-85

Authors: Cadman T, Spain D, Johnston P, Russell A, Mataix-Cols D, Craig M, Deeley Q, Robertson D, Murphy C, Gillan N, Wilson CE, Mendez M, Ecker C, Daly E, Findon J, Glaser K, MRC AIMS Consortium, Happé F, Murphy D

Abstract
Little is known about the symptom profile of obsessive-compulsive disorder (OCD) in individuals who have autism spectrum disorders (ASD). It is also unknown whether self-report questionnaires are useful in measuring OCD in ASD. We sought to describe the symptom profiles of adults with ASD, OCD, and ASD + OCD using the Obsessive Compulsive Inventory-Revised (OCI-R), and to assess the utility of the OCI-R as a screening measure in a high-functioning adult ASD sample. Individuals with ASD (n = 171), OCD (n = 108), ASD + OCD (n = 54) and control participants (n = 92) completed the OCI-R. Individuals with ASD + OCD reported significantly higher levels of obsessive-compulsive symptoms than those with ASD alone. OCD symptoms were not significantly correlated with core ASD repetitive behaviors as measured on the ADI-R or ADOS-G. The OCI-R showed good psychometric properties and corresponded well with clinician diagnosis of OCD. Receiver operating characteristic analysis suggested cut-offs for OCI-R Total and Checking scores that discriminated well between ASD + versus -OCD, and fairly well between ASD-alone and OCD-alone. OCD manifests separately from ASD and is characterized by a different profile of repetitive thoughts and behaviors. The OCI-R appears to be useful as a screening tool in the ASD adult population.

PMID: 25663563 [PubMed - indexed for MEDLINE]

Ephrin-B3 coordinates timed axon targeting and amygdala spinogenesis for innate fear behaviour.

August 30, 2016 - 6:50am
Related Articles

Ephrin-B3 coordinates timed axon targeting and amygdala spinogenesis for innate fear behaviour.

Nat Commun. 2016;7:11096

Authors: Zhu XN, Liu XD, Sun S, Zhuang H, Yang JY, Henkemeyer M, Xu NJ

Abstract
Innate emotion response to environmental stimuli is a fundamental brain function that is controlled by specific neural circuits. Dysfunction of early emotional circuits may lead to neurodevelopmental disorders such as autism and schizophrenia. However, how the functional circuits are formed to prime initial emotional behaviours remain elusive. We reveal here using gene-targeted mutations an essential role for ephrin-B3 ligand-like activity in the development of innate fear in the neonatal brain. We further demonstrate that ephrin-B3 controls axon targeting and coordinates spinogenesis and neuronal activity within the amygdala. The morphological and behavioural abnormalities in ephrin-B3 mutant mice are rescued by conditional knock-in of wild-type ephrin-B3 during the critical period when axon targeting and fear responses are initiated. Our results thus define a key axonal molecule that participates in the wiring of amygdala circuits and helps bring about fear emotion during the important adolescence period.

PMID: 27008987 [PubMed - indexed for MEDLINE]

Robust classification of protein variation using structural modelling and large-scale data integration.

August 30, 2016 - 6:50am
Related Articles

Robust classification of protein variation using structural modelling and large-scale data integration.

Nucleic Acids Res. 2016 Apr 7;44(6):2501-13

Authors: Baugh EH, Simmons-Edler R, Müller CL, Alford RF, Volfovsky N, Lash AE, Bonneau R

Abstract
Existing methods for interpreting protein variation focus on annotating mutation pathogenicity rather than detailed interpretation of variant deleteriousness and frequently use only sequence-based or structure-based information. We present VIPUR, a computational framework that seamlessly integrates sequence analysis and structural modelling (using the Rosetta protein modelling suite) to identify and interpret deleterious protein variants. To train VIPUR, we collected 9477 protein variants with known effects on protein function from multiple organisms and curated structural models for each variant from crystal structures and homology models. VIPUR can be applied to mutations in any organism's proteome with improved generalized accuracy (AUROC .83) and interpretability (AUPR .87) compared to other methods. We demonstrate that VIPUR's predictions of deleteriousness match the biological phenotypes in ClinVar and provide a clear ranking of prediction confidence. We use VIPUR to interpret known mutations associated with inflammation and diabetes, demonstrating the structural diversity of disrupted functional sites and improved interpretation of mutations associated with human diseases. Lastly, we demonstrate VIPUR's ability to highlight candidate variants associated with human diseases by applying VIPUR to de novo variants associated with autism spectrum disorders.

PMID: 26926108 [PubMed - indexed for MEDLINE]

Research sheds light on gene expression differences in 22q11.2 deletion syndrome.

August 30, 2016 - 6:50am
Related Articles

Research sheds light on gene expression differences in 22q11.2 deletion syndrome.

Am J Med Genet A. 2015 Nov;167A(11):x-xi

Authors:

PMID: 26480311 [PubMed - indexed for MEDLINE]

Disorders of carnitine biosynthesis and transport.

August 30, 2016 - 6:50am
Related Articles

Disorders of carnitine biosynthesis and transport.

Mol Genet Metab. 2015 Nov;116(3):107-12

Authors: El-Hattab AW, Scaglia F

Abstract
Carnitine is a hydrophilic quaternary amine that plays a number of essential roles in metabolism with the main function being the transport of long-chain fatty acids from the cytosol to the mitochondrial matrix for β-oxidation. Carnitine can be endogenously synthesized. However, only a small fraction of carnitine is obtained endogenously while the majority is obtained from diet, mainly animal products. Carnitine is not metabolized and is excreted in urine. Carnitine homeostasis is regulated by efficient renal reabsorption that maintains carnitine levels within the normal range despite variabilities in dietary intake. Diseases occurring due to primary defects in carnitine metabolism and homeostasis are comprised in two groups: disorders of carnitine biosynthesis and carnitine transport defect. While the hallmark of carnitine transport defect is profound carnitine depletion, disorders of carnitine biosynthesis do not cause carnitine deficiency due to the fact that both carnitine obtained from diet and efficient renal carnitine reabsorption can maintain normal carnitine levels with the absence of endogenously synthesized carnitine. Carnitine transport defect phenotype encompasses a broad clinical spectrum including metabolic decompensation in infancy, cardiomyopathy in childhood, fatigability in adulthood, or absence of symptoms. The phenotypes associated with the carnitine transport defect result from the unavailability of enough carnitine to perform its functions particularly in fatty acid β-oxidation. Carnitine biosynthetic defects have been recently described and the phenotypic consequences of these defects are still emerging. Although these defects do not result in carnitine deficiency, they still could be associated with pathological phenotypes due to excess or deficiency of intermediate metabolites in the carnitine biosynthetic pathway and potential carnitine deficiency in early stages of life when brain and other organs develop. In addition to these two groups of primary carnitine defects, several metabolic diseases and medical conditions can result in excessive carnitine loss leading to a secondary carnitine deficiency.

PMID: 26385306 [PubMed - indexed for MEDLINE]

Recurrent deletions and duplications of chromosome 2q11.2 and 2q13 are associated with variable outcomes.

August 30, 2016 - 6:50am
Related Articles

Recurrent deletions and duplications of chromosome 2q11.2 and 2q13 are associated with variable outcomes.

Am J Med Genet A. 2015 Nov;167A(11):2664-73

Authors: Riley KN, Catalano LM, Bernat JA, Adams SD, Martin DM, Lalani SR, Patel A, Burnside RD, Innis JW, Rudd MK

Abstract
Copy number variation (CNV) in the long arm of chromosome 2 has been implicated in developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), congenital anomalies, and psychiatric disorders. Here we describe 14 new subjects with recurrent deletions and duplications of chromosome 2q11.2, 2q13, and 2q11.2-2q13. Though diverse phenotypes are associated with these CNVs, some common features have emerged. Subjects with 2q11.2 deletions often exhibit DD, speech delay, and attention deficit hyperactivity disorder (ADHD), whereas those with 2q11.2 duplications have DD, gastroesophageal reflux, and short stature. Congenital heart defects (CHDs), hypotonia, dysmorphic features, and abnormal head size are common in those with 2q13 deletions. In the 2q13 duplication cohort, we report dysmorphic features, DD, and abnormal head size. Two individuals with large duplications spanning 2q11.2-2q13 have dysmorphic features, hypotonia, and DD. This compilation of clinical features associated with 2q CNVs provides information that will be useful for healthcare providers and for families of affected children. However, the reduced penetrance and variable expressivity associated with these recurrent CNVs makes genetic counseling and prediction of outcomes challenging. © 2015 Wiley Periodicals, Inc.

PMID: 26227573 [PubMed - indexed for MEDLINE]

The neurobehavioral and molecular phenotype of Angelman Syndrome.

August 30, 2016 - 6:50am
Related Articles

The neurobehavioral and molecular phenotype of Angelman Syndrome.

Am J Med Genet A. 2015 Nov;167A(11):2623-8

Authors: Wink LK, Fitzpatrick S, Shaffer R, Melnyk S, Begtrup AH, Fox E, Schaefer TL, Mathieu-Frasier L, Ray B, Lahiri D, Horn PA, Erickson CA

Abstract
Angelman Syndrome (AS) is a rare neurodevelopmental disorder associated with developmental delay, speech impairment, gait ataxia, and a unique behavioral profile. AS is caused by loss of maternal expression of the paternally imprinted UBE3A gene. In this study we aim to contribute to understanding of the neurobehavioral phenotype of AS with particular focus on the neuropsychiatric presentation of the disorder. We also undertake initial exploration of brain-derived neurotrophic factor (BDNF) plasma levels in AS. Twelve individuals ages 3 years or older with a confirmed genetic diagnosis of AS underwent detailed medical history, phenotypic characterization, and BDNF plasma sampling. The results of this study demonstrate that individuals with AS suffer from significant developmental delay, impaired adaptive behavior, and sleep disruption. Additionally, hyperactivity/impulsivity appears to be the primary behavioral domain noted in these individuals. The majority of individuals in this project met criteria for autism spectrum disorder on the Autism Diagnostic Observation Schedule (ADOS); however, a negative correlation was noted between ADOS score and developmental age. BDNF plasma levels in AS individuals were significantly elevated compared to neurotypical controls. This is the first report of abnormal BDNF levels in AS, and one that necessitates larger future studies. The results provide a clue to understanding abnormal neuronal development in AS and may help guide future AS research.

PMID: 26219744 [PubMed - indexed for MEDLINE]

Pages