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Drosophila melanogaster: a novel animal model for the behavioral characterization of autism-associated mutations in the dopamine transporter gene.

June 24, 2014 - 7:37am
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Drosophila melanogaster: a novel animal model for the behavioral characterization of autism-associated mutations in the dopamine transporter gene.

Mol Psychiatry. 2013 Dec;18(12):1235

Authors: Hamilton PJ, Campbell NG, Sharma S, Erreger K, Hansen FH, Saunders C, Belovich AN, Sahai MA, Cook EH, Gether U, McHaourab HS, Matthies HJ, Sutcliffe JS, Galli A

PMID: 24253181 [PubMed - indexed for MEDLINE]

Psychiatric assessment of severe presentations in autism spectrum disorders and intellectual disability.

June 24, 2014 - 7:37am
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Psychiatric assessment of severe presentations in autism spectrum disorders and intellectual disability.

Child Adolesc Psychiatr Clin N Am. 2014 Jan;23(1):1-14

Authors: King BH, de Lacy N, Siegel M

Abstract
Children with autism spectrum and related disorders and intellectual disability are not protected from the experience of psychiatric illnesses. Many factors can contribute to exacerbation of existing behavioral symptoms or to the emergence of new psychiatric problems. The psychiatric assessment must thus take into account a range of possible etiologic or contributory factors. The approach outlined in this article highlights the value of assessing 4 broad domains, including diagnostic (genetic) factors, medical considerations, developmental influences, and environmental factors. Examples of how the consideration of each of these domains may inform the diagnostic formulation are highlighted.

PMID: 24231163 [PubMed - indexed for MEDLINE]

Typical and atypical brain development: a review of neuroimaging studies.

June 24, 2014 - 7:37am
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Typical and atypical brain development: a review of neuroimaging studies.

Dialogues Clin Neurosci. 2013 Sep;15(3):359-84

Authors: Dennis EL, Thompson PM

Abstract
In the course of development, the brain undergoes a remarkable process of restructuring as it adapts to the environment and becomes more efficient in processing information. A variety of brain imaging methods can be used to probe how anatomy, connectivity, and function change in the developing brain. Here we review recent discoveries regarding these brain changes in both typically developing individuals and individuals with neurodevelopmental disorders. We begin with typical development, summarizing research on changes in regional brain volume and tissue density, cortical thickness, white matter integrity, and functional connectivity. Space limits preclude the coverage of all neurodevelopmental disorders; instead, we cover a representative selection of studies examining neural correlates of autism, attention deficit/hyperactivity disorder, Fragile X, 22q11.2 deletion syndrome, Williams syndrome, Down syndrome, and Turner syndrome. Where possible, we focus on studies that identify an age by diagnosis interaction, suggesting an altered developmental trajectory. The studies we review generally cover the developmental period from infancy to early adulthood. Great progress has been made over the last 20 years in mapping how the brain matures with MR technology. With ever-improving technology, we expect this progress to accelerate, offering a deeper understanding of brain development, and more effective interventions for neurodevelopmental disorders.

PMID: 24174907 [PubMed - indexed for MEDLINE]

Neuroligin modulates the locomotory dopaminergic and serotonergic neuronal pathways of C. elegans.

June 24, 2014 - 7:37am
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Neuroligin modulates the locomotory dopaminergic and serotonergic neuronal pathways of C. elegans.

Neurogenetics. 2013 Nov;14(3-4):233-42

Authors: Izquierdo PG, Calahorro F, Ruiz-Rubio M

Abstract
Neuroligins are neuronal and neuromuscular transmembrane proteins that have been implicated in autism spectrum disorder and other cognitive diseases. The nlg-1 gene from Caenorhabditis elegans is orthologous to human neuroligin genes. In the nematode, the locomotory rate is mediated by dopaminergic and serotonergic pathways, which result in two different behavioral responses known as basal slowing response (BSR) and enhanced slowing response (ESR), respectively. We report that nlg-1-deficient mutants are defective in both the BSR and ESR behaviors. In addition, we demonstrate that methylphenidate (a dopamine reuptake inhibitor) and fluoxetine (a serotonin reuptake inhibitor), two drugs widely used for the treatment of behavioral disorders in humans, are able to restore the BSR and ESR wild type phenotypes, respectively, in nlg-1 defective mutant nematodes. The abnormal locomotory behavior patterns were rescued in nlg-1-deficient mutant by expressing a cDNA from the human NLGN1 gene under the C. elegans nlg-1 promoter. However, human NLGN1 (R453C) and NLGN1 (D432X) mutant alleles did not rescue any of the two mutant phenotypes. The results indicate that neuroligin is involved in modulating the action of dopamine and serotonin in the nematode and suggest that the functional mechanism underpinning both methylphenidate and fluoxetine in C. elegans might be comparable to that in humans. The neuroligin-deficient mutants may undergo inefficient synaptic transmissions which could affect different traits in the nervous system. In particular, neuroligin might be required for normal neurotransmitters release. The understanding of the mechanisms by which methylphenidate and fluoxetine are able to restore the behavior of these mutants could help to explain the etiology of some human neurological diseases.

PMID: 24100941 [PubMed - indexed for MEDLINE]

Benign infantile convulsions (IC) and subsequent paroxysmal kinesigenic dyskinesia (PKD) in a patient with 16p11.2 microdeletion syndrome.

June 24, 2014 - 7:37am
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Benign infantile convulsions (IC) and subsequent paroxysmal kinesigenic dyskinesia (PKD) in a patient with 16p11.2 microdeletion syndrome.

Neurogenetics. 2013 Nov;14(3-4):251-3

Authors: Weber A, Köhler A, Hahn A, Neubauer B, Müller U

Abstract
Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) is caused by mutations in the gene PRRT2 located in 16p11.2. A deletion syndrome 16p11.2 is well established and is characterized by intellectual disability, speech delay, and autism. PKD/IC, however, is extremely rare in this syndrome. We describe a case of PKD/IC and 16p11.2 deletion syndrome and discuss modifiers of PRRT2 activity to explain the rare concurrence of both syndromes.

PMID: 24100940 [PubMed - indexed for MEDLINE]

The social defeat hypothesis of schizophrenia: an update.

June 24, 2014 - 7:37am
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The social defeat hypothesis of schizophrenia: an update.

Schizophr Bull. 2013 Nov;39(6):1180-6

Authors: Selten JP, van der Ven E, Rutten BP, Cantor-Graae E

Abstract
According to the social defeat (SD) hypothesis, published in 2005, long-term exposure to the experience of SD may lead to sensitization of the mesolimbic dopamine (DA) system and thereby increase the risk for schizophrenia. The hypothesis posits that SD (ie, the negative experience of being excluded from the majority group) is the common denominator of 5 major schizophrenia risk factors: urban upbringing, migration, childhood trauma, low intelligence, and drug abuse. The purpose of this update of the literature since 2005 is to answer 2 questions: (1) What is the evidence that SD explains the association between schizophrenia and these risk factors? (2) What is the evidence that SD leads to sensitization of the mesolimbic DA system? The evidence for SD as the mechanism underlying the increased risk was found to be strongest for migration and childhood trauma, while the evidence for urban upbringing, low intelligence, and drug abuse is suggestive, but insufficient. Some other findings that may support the hypothesis are the association between risk for schizophrenia and African American ethnicity, unemployment, single status, hearing impairment, autism, illiteracy, short stature, Klinefelter syndrome, and, possibly, sexual minority status. While the evidence that SD in humans leads to sensitization of the mesolimbic DA system is not sufficient, due to lack of studies, the evidence for this in animals is strong. The authors argue that the SD hypothesis provides a parsimonious and plausible explanation for a number of epidemiological findings that cannot be explained solely by genetic confounding.

PMID: 24062592 [PubMed - indexed for MEDLINE]

De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder.

June 24, 2014 - 7:37am
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De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder.

Mol Psychiatry. 2013 Dec;18(12):1315-23

Authors: Hamilton PJ, Campbell NG, Sharma S, Erreger K, Herborg Hansen F, Saunders C, Belovich AN, NIH ARRA Autism Sequencing Consortium, Sahai MA, Cook EH, Gether U, McHaourab HS, Matthies HJ, Sutcliffe JS, Galli A

Abstract
De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution at site 356 (hDAT T356M). The dopamine transporter (DAT) is a presynaptic membrane protein that regulates dopaminergic tone in the central nervous system by mediating the high-affinity reuptake of synaptically released DA, making it a crucial regulator of DA homeostasis. Here, we report the first functional, structural and behavioral characterization of an ASD-associated de novo mutation in the hDAT. We demonstrate that the hDAT T356M displays anomalous function, characterized as a persistent reverse transport of DA (substrate efflux). Importantly, in the bacterial homolog leucine transporter, substitution of A289 (the homologous site to T356) with a Met promotes an outward-facing conformation upon substrate binding. In the substrate-bound state, an outward-facing transporter conformation is required for substrate efflux. In Drosophila melanogaster, the expression of hDAT T356M in DA neurons-lacking Drosophila DAT leads to hyperlocomotion, a trait associated with DA dysfunction and ASD. Taken together, our findings demonstrate that alterations in DA homeostasis, mediated by aberrant DAT function, may confer risk for ASD and related neuropsychiatric conditions.

PMID: 23979605 [PubMed - indexed for MEDLINE]

Effects of environmental enrichment on repetitive behaviors in the BTBR T+tf/J mouse model of autism.

June 21, 2014 - 6:09am
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Effects of environmental enrichment on repetitive behaviors in the BTBR T+tf/J mouse model of autism.

Autism Res. 2013 Oct;6(5):337-43

Authors: Reynolds S, Urruela M, Devine DP

Abstract
Lower order and higher order repetitive behaviors have been documented in the BTBR T+tf/J (BTBR) mouse strain, a mouse model that exhibits all three core behavioral domains that define autism. The purpose of this study was to evaluate the effectiveness of environmental enrichment for reducing repetitive behaviors in BTBR mice. Lower order behaviors were captured by assaying the time and sequence of grooming, while higher order behaviors were measured using pattern analysis of an object exploration task from digital recordings. Baseline scores were established at 7 weeks of age, followed by 30 days of housing in either a standard or enriched cage. As expected, BTBR mice spent significantly more time grooming and had a more rigid grooming sequence than control C57BL/6J mice did at baseline. After 30 days of enrichment housing, BTBR mice demonstrated a significant reduction in time spent grooming, resulting in levels that were lower than those exhibited by BTBR mice in standard housing. However, no changes were noted in the rigidity of their grooming sequence. In contrast to previous findings, there was no difference in repetitive patterns of exploration at baseline between BTBR and C57BL/6J mice in the object exploration test. Subsequently, enrichment did not significantly alter the number of repetitive patterns at posttest. Overall, the results suggest that environmental enrichment may be beneficial for reducing the time spent engaging in lower order repetitive behaviors, but may not change the overall quality of the behaviors when they do manifest.

PMID: 23813950 [PubMed - indexed for MEDLINE]

Stem cells as a good tool to investigate dysregulated biological systems in autism spectrum disorders.

June 21, 2014 - 6:09am
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Stem cells as a good tool to investigate dysregulated biological systems in autism spectrum disorders.

Autism Res. 2013 Oct;6(5):354-61

Authors: Griesi-Oliveira K, Sunaga DY, Alvizi L, Vadasz E, Passos-Bueno MR

Abstract
Identification of the causes of autism spectrum disorders (ASDs) is hampered by their genetic heterogeneity; however, the different genetic alterations leading to ASD seem to be implicated in the disturbance of common molecular pathways or biological processes. In this scenario, the search for differentially expressed genes (DEGs) between ASD patients and controls is a good alternative to identify the molecular etiology of such disorders. Here, we employed genome-wide expression analysis to compare the transcriptome of stem cells of human exfoliated deciduous teeth (SHEDs) of idiopathic autistic patients (n = 7) and control samples (n = 6). Nearly half of the 683 identified DEGs are expressed in the brain (P = 0.003), and a significant number of them are involved in mechanisms previously associated with ASD such as protein synthesis, cytoskeleton regulation, cellular adhesion and alternative splicing, which validate the use of SHEDs to disentangle the causes of autism. Autistic patients also presented overexpression of genes regulated by androgen receptor (AR), and AR itself, which in turn interacts with CHD8 (chromodomain helicase DNA binding protein 8), a gene recently shown to be associated with the cause of autism and found to be upregulated in some patients tested here. These data provide a rationale for the mechanisms through which CHD8 leads to these diseases. In summary, our results suggest that ASD share deregulated pathways and revealed that SHEDs represent an alternative cell source to be used in the understanding of the biological mechanisms involved in the etiology of ASD.

PMID: 23801657 [PubMed - indexed for MEDLINE]

Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis.

June 21, 2014 - 6:09am
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Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis.

Autism Res. 2013 Oct;6(5):384-92

Authors: Pu D, Shen Y, Wu J

Abstract
Methylenetetrahydrofolate reductase (MTHFR) is essential for DNA biosynthesis and the epigenetic process of DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and cancers. However, reports on the association of MTHFR polymorphisms with autism spectrum disorders (ASD) are inconclusive. Therefore, we investigated the relationship of the MTHFR polymorphisms (C677T and A1298C) and the risk of ASD by meta-analysis. Up to December 2012, eight case-control studies involving 1672 patients with ASD and 6760 controls were included for meta-analysis. The results showed that the C677T polymorphism was associated with significantly increased ASD risk in all the comparison models [T vs. C allele (frequency of allele): odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.09-1.85; CT vs. CC (heterozygote): OR = 1.48, 95% CI: 1.09-2.00; TT vs. CC (homozygote): OR = 1.86, 95% CI: 1.08-3.20; CT+TT vs. CC (dominant model): OR = 1.56, 95% CI: 1.12-2.18; and TT vs. CC+CT (recessive model): OR = 1.51, 95% CI: 1.02-2.22], whereas the A1298C polymorphism was found to be significantly associated with reduced ASD risk but only in a recessive model (CC vs. AA+AC: OR = 0.73, 95% CI: 0.56-0.97). In addition, we stratified the patient population based on whether they were from a country with food fortification of folic acid or not. The meta-analysis showed that the C677T polymorphism was found to be associated with ASD only in children from countries without food fortification. Our study indicated that the MTHFR C677T polymorphism contributes to increased ASD risk, and periconceptional folic acid may reduce ASD risk in those with MTHFR 677C>T polymorphism.

PMID: 23653228 [PubMed - indexed for MEDLINE]

Network Plasticity in Adaptive Filtering and Behavioral Habituation.

June 20, 2014 - 8:08am

Network Plasticity in Adaptive Filtering and Behavioral Habituation.

Neuron. 2014 Jun 18;82(6):1216-1229

Authors: Ramaswami M

Abstract
The ability of organisms to seamlessly ignore familiar, inconsequential stimuli improves their selective attention and response to salient features of the environment. Here, I propose that this fundamental but unexplained phenomenon substantially derives from the ability of any pattern of neural excitation to create an enhanced inhibitory (or "negative") image of itself through target-specific scaling of inhibitory inputs onto active excitatory neurons. Familiar stimuli encounter strong negative images and are therefore less likely to be transmitted to higher brain centers. Integrating historical and recent observations, the negative-image model described here provides a mechanistic framework for understanding habituation, which is connected to ideas on dynamic predictive coding. In addition, it suggests insights for understanding autism spectrum disorders. VIDEO ABSTRACT:

PMID: 24945768 [PubMed - as supplied by publisher]

Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice.

June 20, 2014 - 8:08am

Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice.

Genome Med. 2014;6(4):29

Authors: Doherty JL, Owen MJ

Abstract
Psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder, attention-deficit/hyperactivity disorder and autism spectrum disorder are common and result in significant morbidity and mortality. Although currently classified into distinct disorder categories, they show clinical overlap and familial co-aggregation, and share genetic risk factors. Recent advances in psychiatric genomics have provided insight into the potential mechanisms underlying the overlap between these disorders, implicating genes involved in neurodevelopment, synaptic plasticity, learning and memory. Furthermore, evidence from copy number variant, exome sequencing and genome-wide association studies supports a gradient of neurodevelopmental psychopathology indexed by mutational load or mutational severity, and cognitive impairment. These findings have important implications for psychiatric research, highlighting the need for new approaches to stratifying patients for research. They also point the way for work aiming to advance our understanding of the pathways from genotype to clinical phenotype, which will be required in order to inform new classification systems and to develop novel therapeutic strategies.

PMID: 24944580 [PubMed - as supplied by publisher]

Evidence of Reproductive Stoppage in Families With Autism Spectrum Disorder: A Large, Population-Based Cohort Study.

June 20, 2014 - 8:08am

Evidence of Reproductive Stoppage in Families With Autism Spectrum Disorder: A Large, Population-Based Cohort Study.

JAMA Psychiatry. 2014 Jun 18;

Authors: Hoffmann TJ, Windham GC, Anderson M, Croen LA, Grether JK, Risch N

Abstract
Importance: Few studies have examined the curtailment of reproduction (ie, stoppage) after the diagnosis of a child with autism spectrum disorder (ASD).
Objective: To examine stoppage in a large, population-based cohort of families in which a child has received a diagnosis of ASD.
Design, Setting, and Participants: Individuals with ASD born from January 1, 1990, through December 31, 2003, were identified in the California Department of Developmental Services records, which were then linked to state birth certificates to identify full sibs and half-sibs and to obtain information on birth order and demographics. A total of 19 710 case families in which the first birth occurred within the study period was identified. These families included 39 361 individuals (sibs and half-sibs). Control individuals were randomly sampled from birth certificates and matched 2:1 to cases by sex, birth year, and maternal age, self-reported race/ethnicity, and county of birth after removal of children receiving services from the California Department of Developmental Services. Using similar linkage methods as for case families, 36 215 pure control families (including 75 724 total individuals) were identified that had no individuals with an ASD diagnosis.
Exposures: History of affected children.
Main Outcomes and Measures: Stoppage was investigated by comparing the reproductive behaviors of parents after the birth of a child with ASD vs an unaffected child using a survival analysis framework for time to next birth and adjusting for demographic variables.
Results: For the first few years after the birth of a child with ASD, the parents' reproductive behavior was similar to that of control parents. However, birth rates differed in subsequent years; overall, families whose first child had ASD had a second child at a rate of 0.668 (95% CI, 0.635-0.701) that of control families, adjusted for birth year, birth weight, maternal age, and self-reported maternal race/ethnicity. Results were similar when a later-born child was the first affected child in the family. Reproductive curtailment was slightly stronger among women who changed partners (relative rate for second-born children, 0.553 [95% CI, 0.498-0.614]).
Conclusions and Relevance: These results provide the first quantitative assessment and convincing statistical evidence of reproductive stoppage related to ASD. These findings have implications for recurrence risk estimation and genetic counseling.

PMID: 24942798 [PubMed - as supplied by publisher]

[Genetic analysis and genes relating synaptic function for autism spectrum disorder].

June 19, 2014 - 7:47am
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[Genetic analysis and genes relating synaptic function for autism spectrum disorder].

No To Hattatsu. 2014 Mar;46(2):125-30

Authors: Yamagata T, Matsumoto A, Nagata K

PMID: 24738190 [PubMed - indexed for MEDLINE]

Clinical neurogenetics: autism spectrum disorders.

June 19, 2014 - 7:47am
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Clinical neurogenetics: autism spectrum disorders.

Neurol Clin. 2013 Nov;31(4):951-68

Authors: Mehta SQ, Golshani P

Abstract
Autism spectrum disorders are neurodevelopmental disorders characterized by deficits in social interactions, communication, and repetitive or restricted interests. There is strong evidence that de novo or inherited genetic alterations play a critical role in causing Autism Spectrum Disorders, but non-genetic causes, such as in utero infections, may also play a role. Magnetic resonance imaging based and autopsy studies indicate that early rapid increase in brain size during infancy could underlie the deficits in a large subset of subjects. Clinical studies show benefits for both behavioral and pharmacological treatment strategies. Genotype-specific treatments have the potential for improving outcome in the future.

PMID: 24176418 [PubMed - indexed for MEDLINE]

Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders.

June 19, 2014 - 7:47am
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Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders.

Mol Neurobiol. 2013 Dec;48(3):465-89

Authors: Bessa C, Maciel P, Rodrigues AJ

Abstract
Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.

PMID: 23494747 [PubMed - indexed for MEDLINE]

Large inverted duplications in the human genome form via a fold-back mechanism.

June 18, 2014 - 6:57am
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Large inverted duplications in the human genome form via a fold-back mechanism.

PLoS Genet. 2014 Jan;10(1):e1004139

Authors: Hermetz KE, Newman S, Conneely KN, Martin CL, Ballif BC, Shaffer LG, Cody JD, Rudd MK

Abstract
Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. For half of the rearrangements in our study, we sequenced at least one breakpoint junction. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted sequences are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a "fold-back" intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the fold-back loop. This process can lead to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes.

PMID: 24497845 [PubMed - indexed for MEDLINE]

Genetic variants of neurotransmitter-related genes and miRNAs in Egyptian autistic patients.

June 18, 2014 - 6:57am
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Genetic variants of neurotransmitter-related genes and miRNAs in Egyptian autistic patients.

ScientificWorldJournal. 2013;2013:670621

Authors: Salem AM, Ismail S, Zarouk WA, Abdul Baky O, Sayed AA, Abd El-Hamid S, Salem S

Abstract
Autism is a neurodevelopmental disorder with indisputable evidence for a genetic component. This work studied the association of autism with genetic variations in neurotransmitter-related genes, including MAOA uVNTR, MAOB rs1799836, and DRD2 TaqI A in 53 autistic patients and 30 healthy individuals. The study also analyzed sequence variations of miR-431 and miR-21. MAOA uVNTR was genotyped by PCR, MAOB and DRD2 polymorphisms were analyzed by PCR-based RFLP, and miR-431 and miR-21 were sequenced. Low expressing allele of MAOA uVNTR was frequently higher in female patients compared to that in controls (OR = 2.25). MAOB G allele frequency was more significantly increased in autistic patients than in controls (P < 0.001 for both males and females). DRD2 A1+ genotype increased autism risk (OR = 5.1). Severity of autism tends to be slightly affected by MAOA/B genotype. Plasma MAOB activity was significantly reduced in G than in A allele carrying males. There was no significant difference in patients and maternal plasma MAOA/B activity compared to controls. Neither mutations nor SNPs in miR-431 and miR-21 were found among studied patients. This study threw light on some neurotransmitter-related genes suggesting their potential role in Autism pathogenesis that warrants further studies and much consideration.

PMID: 24453887 [PubMed - indexed for MEDLINE]

Cognitive styles in depressed children with and without comorbid conduct disorder.

June 17, 2014 - 6:22am

Cognitive styles in depressed children with and without comorbid conduct disorder.

J Adolesc. 2014 Jul;37(5):622-31

Authors: Schepman K, Fombonne E, Collishaw S, Taylor E

Abstract
Little is known about patterns of cognitive impairment in depression comorbid with conduct disorder. The study included clinically depressed children with (N = 23) or without conduct disorder (N = 29), and controls without psychiatric disorder (N = 37). Cognitive biases typical of depression and patterns of social information processing were assessed. Both depressed groups had substantially higher rates of negative cognitive distortions, attributional biases and ruminative responses than non-depressed children. Children in the comorbid group made more hostile attributions and suggested more aggressive responses for dealing with threatening social situations, whilst children with depression only were more likely to be unassertive. Depression has a number of similar depressotypic cognitive biases whether or not complicated by conduct disorder, and may be potentially susceptible to similar interventions. The results also highlight the importance of recognising social information processing deficits when they occur and targeting those too, especially in comorbid presentations.

PMID: 24931565 [PubMed - in process]

The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour and neuronal outgrowth.

June 17, 2014 - 6:22am
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The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour and neuronal outgrowth.

Hum Mol Genet. 2013 Dec 1;22(23):4673-87

Authors: Jolly LA, Homan CC, Jacob R, Barry S, Gecz J

Abstract
Loss-of-function mutations in UPF3B result in variable clinical presentations including intellectual disability (ID, syndromic and non-syndromic), autism, childhood onset schizophrenia and attention deficit hyperactivity disorder. UPF3B is a core member of the nonsense-mediated mRNA decay (NMD) pathway that functions to rapidly degrade transcripts with premature termination codons (PTCs). Traditionally identified in thousands of human diseases, PTCs were recently also found to be part of 'normal' genetic variation in human populations. Furthermore, many human transcripts have naturally occurring regulatory features compatible with 'endogenous' PTCs strongly suggesting roles of NMD beyond PTC mRNA control. In this study, we investigated the role of Upf3b and NMD in neural cells. We provide evidence that suggests Upf3b-dependent NMD (Upf3b-NMD) is regulated at multiple levels during development including regulation of expression and sub-cellular localization of Upf3b. Furthermore, complementary expression of Upf3b, Upf3a and Stau1 stratify the developing dorsal telencephalon, suggesting that alternative NMD, and the related Staufen1-mediated mRNA decay (SMD) pathways are differentially employed. A loss of Upf3b-NMD in neural progenitor cells (NPCs) resulted in the expansion of cell numbers at the expense of their differentiation. In primary hippocampal neurons, loss of Upf3b-NMD resulted in subtle neurite growth effects. Our data suggest that the cellular consequences of loss of Upf3b-NMD can be explained in-part by changes in expression of key NMD-feature containing transcripts, which are commonly deregulated also in patients with UPF3B mutations. Our research identifies novel pathological mechanisms of UPF3B mutations and at least partly explains the clinical phenotype of UPF3B patients.

PMID: 23821644 [PubMed - indexed for MEDLINE]

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