1. Alvares GA, Balleine BW, Whittle L, Guastella AJ. {{Reduced goal-directed action control in autism spectrum disorder}}. {Autism Res}. 2016.
Autism spectrum disorder (ASD) is a group of heterogeneous neurodevelopmental conditions associated with persistent, stereotyped or repetitive actions, and patterns of interest that are maintained in spite of possible negative outcomes. The aim of the present study was to investigate whether impairments in the ability to execute flexible goal-directed actions may be an underlying feature in ASD contributing to these symptoms. Young adults diagnosed with ASD were recruited along with controls and adults with social anxiety disorder (SAD). Participants were trained to make keyboard actions for food outcomes and then subsequently allowed to consume one outcome till satiety. As expected, this outcome devaluation procedure reduced subsequent responding for actions predicting the devalued outcome, while maintaining responding on the other still-valued action, in controls. However, both ASD and SAD participants were unable to demonstrate flexible goal-directed actions, and were insensitive to the change in outcome value on subsequent action control. This behavioral deficit was not due to impairments in appropriate contingency awareness, as all groups rated the devalued food outcome as less pleasant after devaluation. A lack of control over actions may underlie persistent and habitual actions in anxiety-inducing contexts typical in both ASD and SAD, such as avoidance and safety behaviors. Using a translational behavioral paradigm, this study demonstrated that individuals with ASD are unable to use changes in the environment to flexibly update their behavior in the same context. This reduced behavioral control may underlie persistence of intrusive actions and restricted inflexible cognition, representing a specific area for targeted behavioral interventions. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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2. Bohland JW. {{Toward a Multimodal, Multiscale Understanding of White Matter Abnormalities in Autism Spectrum Disorder}}. {Biol Psychiatry}. 2016; 79(8): e47-8.
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3. Bruno JL, Hosseini SM, Saggar M, Quintin EM, Raman MM, Reiss AL. {{Altered Brain Network Segregation in Fragile X Syndrome Revealed by Structural Connectomics}}. {Cereb Cortex}. 2016.
Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism spectrum disorder, is associated with significant behavioral, social, and neurocognitive deficits. Understanding structural brain network topology in FXS provides an important link between neurobiological and behavioral/cognitive symptoms of this disorder. We investigated the connectome via whole-brain structural networks created from group-level morphological correlations. Participants included 100 individuals: 50 with FXS and 50 with typical development, age 11-23 years. Results indicated alterations in topological properties of structural brain networks in individuals with FXS. Significantly reduced small-world index indicates a shift in the balance between network segregation and integration and significantly reduced clustering coefficient suggests that reduced local segregation shifted this balance. Caudate and amygdala were less interactive in the FXS network further highlighting the importance of subcortical region alterations in the neurobiological signature of FXS. Modularity analysis indicates that FXS and typically developing groups’ networks decompose into different sets of interconnected sub networks, potentially indicative of aberrant local interconnectivity in individuals with FXS. These findings advance our understanding of the effects of fragile X mental retardation protein on large-scale brain networks and could be used to develop a connectome-level biological signature for FXS.
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4. Chen MH, Lan WH, Hsu JW, Huang KL, Su TP, Li CT, Lin WC, Tsai CF, Tsai SJ, Lee YC, Chen YS, Pan TL, Chang WH, Chen TJ, Bai YM. {{Risk of Developing Type 2 Diabetes in Adolescents and Young Adults With Autism Spectrum Disorder: A Nationwide Longitudinal Study}}. {Diabetes Care}. 2016.
OBJECTIVE: Studies have suggested the association between autism spectrum disorder (ASD) and type 2 diabetes mellitus (DM)-related risk factors, such as obesity and dyslipidemia. However, the association between ASD and type 2 DM remains unknown. RESEARCH DESIGN AND METHODS: We used the Taiwan National Health Insurance Research Database for enrolling 6,122 adolescents and young adults with ASD and 24,488 age- and sex-matched control subjects between 2002 and 2009 and monitored them until the end of 2011. Participants who developed type 2 DM during the follow-up period were identified. RESULTS: Adolescents (hazard ratio [HR] 2.71 [95% CI 1.64-4.48]) and young adults (HR 5.31 [95% CI 2.85-9.90]) with ASD had a higher risk of developing type 2 DM than those without ASD, after adjustment for demographic data, atypical antipsychotics use, and medical comorbidities. Sensitivity analyses after excluding first year (HR 3.03 [95% CI 2.03-4.51]) and first 3-year (HR 2.62 [95% CI 1.62-4.23]) observation periods were consistent. Short-term (HR 1.97 [95% CI 1.20-3.23]) and long-term (HR 1.64 [95% CI 1.02-2.63]) use of atypical antipsychotics were associated with a higher likelihood of subsequent type 2 DM. CONCLUSIONS: Adolescents and young adults with ASD were more likely to develop type 2 DM during the follow-up. In addition, those with ASD using atypical antipsychotics exhibited a high risk. Therefore, further research is necessary to investigate the common pathophysiology of ASD and type 2 DM.
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5. Chen SF, Chien YL, Wu CT, Shang CY, Wu YY, Gau SS. {{Deficits in executive functions among youths with autism spectrum disorders: an age-stratified analysis}}. {Psychol Med}. 2016: 1-14.
BACKGROUND: Impaired executive function (EF) is suggested to be one of the core features in individuals with autism spectrum disorders (ASD); however, little is known about whether the extent of worse EF in ASD than typically developing (TD) controls is age-dependent. We used age-stratified analysis to reveal this issue. METHOD: We assessed 111 youths with ASD (aged 12.5 +/- 2.8 years, male 94.6%) and 114 age-, and sex-matched TD controls with Digit Span and four EF tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB): Spatial Span (SSP), Spatial Working Memory (SWM), Stockings of Cambridge (SOC), and Intradimensional/Extradimensional Shift Test (I/ED). RESULTS: Compared to TD controls, youths with ASD performed poorer on the Digit Span, SWM, SOC, and I/ED tasks. The performance of all the tasks improved with age for both groups. Age-stratified analyses were conducted due to significant age x group interactions in visuospatial planning (SOC) and set-shifting (I/ED) and showed that poorer performance on these two tasks in ASD than TD controls was found only in the child (aged 8-12 years) rather than the adolescent (aged 13-18 years) group. By contrast, youths with ASD had impaired working memory, regardless of age. The increased magnitude of group difference in visuospatial planning (SOC) with increased task demands differed between the two age groups but no age moderating effect on spatial working memory. CONCLUSIONS: Our findings support deficits in visuospatial working memory and planning in youths with ASD; however, worse performance in set-shifting may only be demonstrated in children with ASD.
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6. Di Marco B, Bonaccorso CM, Aloisi E, D’Antoni S, Catania MV. {{Neuro-inflammatory mechanisms in developmental disorders associated with Intellectual Disability and Autism Spectrum Disorder: a neuro-immune perspective}}. {CNS Neurol Disord Drug Targets}. 2016.
Intellectual disability (ID) and autism are present in several neurodevelopmental disorders and are often associated in genetic syndromes, such as Fragile X and Rett syndromes. While most evidence indicates that a genetic component plays an important role in the aetiology of both autism and ID, a number of studies suggest that immunological dysfunctions may participate in the pathophysiology of these disorders. Brain-specific autoantibodies have been detected in the sera of many autistic children and autoimmune disorders are increased in families of children with autism. Furthermore, cytokine imbalance has been reported in children with autism. These results may reflect an inappropriate immune response to environmental factors, such as infectious or toxic exposure. The role of microglia as sensors of pre- and post-natal environmental stimuli and its involvement in the regulation of synaptic connectivity, maturation of brain circuitry and neurogenesis has recently emerged. An abnormal immune response during critical windows of development and consequent abnormal production of neuro-inflammatory mediators may have an impact on the function and structure of brain and can play a role in the pathogenesis of non syndromic autism. Recent evidence suggests an involvement of neuro-inflammation also in syndromic forms of autism and ID. Immune dysregulation has been found in children with Fragile X syndrome and an intrinsic microglia dysfunction has been recently reported in Rett syndrome. The present review summarizes the current literature suggesting that neuro-inflammatory mechanisms may contribute to the pathogenesis of different ID- and autism-associated disorders, thus representing common pathophysiological pathways and potential therapeutic targets.
7. Erturk O, Korkmaz B, Alev G, Demirbilek V, Kiziltan M. {{Startle and blink reflex in high functioning autism}}. {Neurophysiol Clin}. 2016.
An important clinical feature of autism is the presence of atypical responses to sensory stimuli. In this study, we investigated if high functioning autistic patients had abnormalities in the blink reflex and the startle reaction to auditory or somatosensory stimuli. Fourteen patients aged between 7 and 16 years were included in the study. We found a longer latency of the blink reflex, an increased duration and amplitude of the auditory startle reaction and a lower presence rate of the somatosensorial startle reaction in autistic patients. To better define the sensorial characteristics of the disease could improve the therapeutic management of children with autism spectrum disorder.
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8. Freyberg J, Robertson CE, Baron-Cohen S. {{Typical magnitude and spatial extent of crowding in autism}}. {J Vis}. 2016; 16(5): 17.
Enhanced spatial processing of local visual details has been reported in individuals with autism spectrum conditions (ASC), and crowding is postulated to be a mechanism that may produce this ability. However, evidence for atypical crowding in ASC is mixed, with some studies reporting a complete lack of crowding in autism and others reporting a typical magnitude of crowding between individuals with and without ASC. Here, we aim to disambiguate these conflicting results by testing both the magnitude and the spatial extent of crowding in individuals with ASC (N = 25) and age- and IQ-matched controls (N = 23) during an orientation discrimination task. We find a strong crowding effect in individuals with and without ASC, which falls off as the distance between target and flanker is increased. Both the magnitude and the spatial range of this effect were comparable between individuals with and without ASC. We also find typical (uncrowded) orientation discrimination thresholds in individuals with ASC. These findings suggest that the spatial extent of crowding is unremarkable in ASC, and is therefore unlikely to account for the visual symptoms reported in individuals with the diagnosis.
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9. Furukawa TA. {{Diagnosing autism spectrum disorder (ASD) among adults}}. {Evid Based Ment Health}. 2016.
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10. Gimbler Berglund I, Huus K, Enskar K, Faresjo M, Bjorkman B. {{Perioperative and Anesthesia Guidelines for Children with Autism: A Nationwide Survey from Sweden}}. {J Dev Behav Pediatr}. 2016.
OBJECTIVE: The overall aim of this study was to describe the current set of guidelines for the preparation and care for children with autism spectrum disorder (ASD) in the perioperative setting across Sweden and explore the content of these guidelines in detail. METHOD: An online questionnaire was distributed to the chairpersons of all anesthesia departments (n = 68) and pediatric departments (n = 38) throughout Sweden. Follow-up phone calls were made to those departments that did not return the questionnaire. The presence of guidelines was analyzed through descriptive statistics. These guidelines and comments on routines used in these departments were analyzed inspired by conventional content analysis. RESULTS: Seven of the 68 anesthesia departments and none of the 38 pediatric departments across Sweden have guidelines for preparing and/or administering care to children with ASD within the perioperative setting. From the guidelines and routines used, 3 categories emerge: « lacking the necessary conditions, » « no extra considerations needed, » and « care with specific consideration for children with ASD. » These 3 categories span a continuum in the care. In the first category, the anesthesia induction could result in the child with ASD being physically restrained. In the last category, the entire encounter with the health care service would be adapted to the specific needs of the child. CONCLUSION: There is a lack of evidence-based guidelines specifically designed to meet the needs of children with ASD in the preoperative period in Sweden. Further research is needed to understand if children with ASD would benefit from evidence-based guidelines.
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11. Kenkel WM, Yee JR, Moore K, Madularu D, Kulkarni P, Gamber K, Nedelman M, Ferris CF. {{Functional magnetic resonance imaging in awake transgenic fragile X rats: evidence of dysregulation in reward processing in the mesolimbic/habenular neural circuit}}. {Transl Psychiatry}. 2016; 6: e763.
Anxiety and social deficits, often involving communication impairment, are fundamental clinical features of fragile X syndrome. There is growing evidence that dysregulation in reward processing is a contributing factor to the social deficits observed in many psychiatric disorders. Hence, we hypothesized that transgenic fragile X mental retardation 1 gene (fmr1) KO (FX) rats would display alterations in reward processing. To this end, awake control and FX rats were imaged for changes in blood oxygen level dependent (BOLD) signal intensity in response to the odor of almond, a stimulus to elicit the innate reward response. Subjects were ‘odor naive’ to this evolutionarily conserved stimulus. The resulting changes in brain activity were registered to a three-dimensional segmented, annotated rat atlas delineating 171 brain regions. Both wild-type (WT) and FX rats showed robust brain activation to a rewarding almond odor, though FX rats showed an altered temporal pattern and tended to have a higher number of voxels with negative BOLD signal change from baseline. This pattern of greater negative BOLD was especially apparent in the Papez circuit, critical to emotional processing and the mesolimbic/habenular reward circuit. WT rats showed greater positive BOLD response in the supramammillary area, whereas FX rats showed greater positive BOLD response in the dorsal lateral striatum, and greater negative BOLD response in the retrosplenial cortices, the core of the accumbens and the lateral preoptic area. When tested in a freely behaving odor-investigation paradigm, FX rats failed to show the preference for almond odor which typifies WT rats. However, FX rats showed investigation profiles similar to WT when presented with social odors. These data speak to an altered processing of this highly salient novel odor in the FX phenotype and lend further support to the notion that altered reward systems in the brain may contribute to fragile X syndrome symptomology.
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12. Khan SA, Narendra AR, Mushtaq G, Zahran SA, Khan S, Kamal MA. {{Alzheimer’s disease and Autistic Spectrum Disorder: Is there any Association?}}. {CNS Neurol Disord Drug Targets}. 2016.
Autism spectrum disorder (ASD) and Alzheimer’s disease (AD) are neurodevelopmental and neurodegenerative disorders respectively, with devastating effects not only on the individual but also on the society. Collectively, a number of factors contribute to the expression of ASD and AD. It is of utmost curiosity that these disorders express at different stages of life and there is an involvement of certain susceptible genes. This genetic basis makes the background of common associations like memory deficits, cognition changes, demyelination, oxidative stress and inflammation, an integral part of both disorders. Modern technology resulting in genetically modified crops and increase in gadgets emitting electromagnetic frequencies have resulted in enhanced risks for neurological dysfunctions and disorders like ASD and AD. Subsequent advances in the psychological, pharmacological, biochemical and nutritional aspects of the disorders have resulted in the development of newer therapeutic approaches. The common clinical features like language impairment, executive functions, and motor problems have been discussed along with the patho-physiological changes, role of DNA methylation, myelin development, and heavy metals in the expression of these disorders. Psycho-pharmacological and nutritional approaches towards the reduction and management of risk factors have gained attention from the researchers in recent years. Current major therapies either target the inflammatory pathways or reduce cellular oxidative stress. This contribution focuses on the commonalities of the two disorders.
13. Kok FM, Groen Y, Becke M, Fuermaier AB, Tucha O. {{Self-Reported Empathy in Adult Women with Autism Spectrum Disorders – A Systematic Mini Review}}. {PLoS One}. 2016; 11(3): e0151568.
INTRODUCTION: There is limited research on Autism Spectrum Disorders (ASD) in females. Although the empathy construct has been examined thoroughly in autism, little attention has been paid to empathy in adult women with this condition or to gender differences within the disorder. OBJECTIVE: Self-reported empathy in adult women with ASD was examined and compared to that of typically developed men and women as well as to men with this condition. METHODS: Online databases were searched for articles investigating self-reported empathy among adult women with ASD. Only six studies comparing women to men were identified. RESULTS: All studies found women with an ASD to report lower levels of empathy than typically developed women, and typically developed men, but similar levels to men with this condition. CONCLUSION: The self-reported empathic ability of women diagnosed with ASD resembles that of their male counterparts most closely; they show a hypermasculinisation in empathy. This is particularly surprising considering the large gender difference in empathy in the general population. DISCUSSION: One of the limitations of this review is that the current diagnostic criteria for ASD are oriented towards male-specific behaviour and fail to integrate gender specific characteristics. Hence, women diagnosed with ASD are likely to be at the male end of the continuum. The suggested hypermasculinisation of women on the spectrum, as evident from this review, may therefore be exaggerated due to a selection bias.
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14. McDonald NM, Baker JK, Messinger DS. {{Oxytocin and Parent-Child Interaction in the Development of Empathy Among Children at Risk for Autism}}. {Dev Psychol}. 2016.
This longitudinal study investigated whether variation in the oxytocin receptor gene (OXTR) and early parent-child interactions predicted later empathic behavior in 84 toddlers at high or low familial risk for autism spectrum disorder. Two well-studied OXTR single-nucleotide polymorphisms, rs53576 and rs2254298, were examined. Parent-child interaction was measured at 15 and 18 months of age during free play sessions. Empathy was measured at 24 and 30 months using a response to parental distress paradigm. While there was no direct association between parent-child interaction quality or OXTR and empathy, rs53576 moderated the relation between interaction quality and empathy. Results suggest that the interplay between OXTR and early parent-child interactions predicts individual differences in empathy in children at varying risk for atypical social development. Findings are consonant with a differential susceptibility model in which an OXTR variant may increase the social salience of interaction processes for specific allele carriers. These results increase our understanding of predictors of empathy development in young children with a wide range of social outcomes. (PsycINFO Database Record
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15. Qiu T, Chang C, Li Y, Qian L, Xiao CY, Xiao T, Xiao X, Xiao YH, Chu KK, Lewis MH, Ke X. {{Two years changes in the development of caudate nucleus are involved in restricted repetitive behaviors in 2-5-year-old children with autism spectrum disorder}}. {Dev Cogn Neurosci}. 2016; 19: 137-43.
Caudate nucleus volume is enlarged in autism spectrum disorder (ASD) and is associated with restricted and repetitive behaviors (RRBs). However, the trajectory of caudate nucleus volume in RRBs of young children remains unclear. Caudate nucleus volume was measured in 36 children with ASD and 18 matched 2-3-year-old subjects with developmentally delayed (DD) at baseline (Time 1) and at 2-year follow-up (Time 2). The differential growth rate in caudate nucleus volume was calculated. Further, the relationships between the development of caudate nucleus volume and RRBs were analyzed. Our results showed that caudate nucleus volume was significantly larger in the ASD group at both time points and the magnitude of enlargement was greater at Time 2. The rate of caudate nucleus growth during this 2-year interval was faster in children with ASD than DD. Right caudate nucleus volume growth was negatively correlated with RRBs. Findings from this study suggest developmental abnormalities of caudate nucleus volume in ASD. Longitudinal MRI studies are needed to explore the correlation between atypical growth patterns of caudate nucleus and phenotype of RRBs.
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16. Robinson EB, St Pourcain B, Anttila V, Kosmicki JA, Bulik-Sullivan B, Grove J, Maller J, Samocha KE, Sanders SJ, Ripke S, Martin J, Hollegaard MV, Werge T, Hougaard DM, Neale BM, Evans DM, Skuse D, Mortensen PB, Borglum AD, Ronald A, Smith GD, Daly MJ. {{Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population}}. {Nat Genet}. 2016.
Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.
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17. Rose SA, Djukic A, Jankowski JJ, Feldman JF, Rimler M. {{Aspects of Attention in Rett Syndrome}}. {Pediatr Neurol}. 2016; 57: 22-8.
BACKGROUND: We sought to examine fundamental aspects of attention in children with Rett syndrome, a severely disabling neurodevelopmental disorder caused by spontaneous mutations in the X-linked MECP2 gene. To gauge their attention, we used eye tracking, which bypasses the profound impairments in expressive language and hand use in Rett syndrome. We report two aspects of attention-shifting and sustaining-basic abilities known to drive cognitive growth. METHODS: Two groups were compared: those with Rett syndrome (N = 20; 3-15 years) and a typically developing comparison group (N = 14; 3-16 years), using a task in which an attractive central stimulus was followed, after a short gap, by a dynamic target presented to one side. Time to shift to the target location (reactive and anticipatory saccades) and time fixating the target were assessed. RESULTS: Children with Rett syndrome were consistently slower to shift (largely because of fewer anticipations); their reactive saccades were also slower than those of typically developing children, but not significantly so. The Rett syndrome group spent considerable time looking at the target (over 75% of available time), although significantly less so than the typically developing group. CONCLUSIONS: These findings indicate that children with Rett syndrome could maintain attention on a stimulus and orient relatively quickly to the appearance of a target in the visual field. However, they had difficulty in anticipating predictable events, a difficulty in endogenous attention that is likely to have deleterious implications for executive functioning.
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18. Santosh P, Tarver J, Gibbons F, Vitoratou S, Simonoff E. {{Protocol for the development and validation of a questionnaire to assess concerning behaviours and mental health in individuals with autism spectrum disorders: the Assessment of Concerning Behaviour (ACB) scale}}. {BMJ Open}. 2016; 6(3): e010693.
INTRODUCTION: Co-occurring psychiatric conditions and concerning behaviours are prevalent in individuals with autism spectrum disorders (ASD), and are likely to be detrimental to functioning and long-term outcomes. The cognitive rigidity and deficits in emotional literacy and verbal behaviour that commonly occur in ASD can adversely affect clinicians’ confidence to identify concerning behaviours and mental health problems. There is a need to develop a measure that is tailored towards individuals with ASD, and differentiates between symptoms of psychopathology and core ASD symptoms. Furthermore, it should be modified to capture internalising symptoms that individuals with ASD may find difficult or be unable to verbalise. This protocol describes the intended development and validation of the Assessment of Concerning Behaviour (ACB) scale. The ACB will aim to be a multidimensional measure of concerning behaviours in ASD incorporating self-report, parent/carer, teacher/employer and clinician report versions that can be used across the lifespan and spectrum of intellectual ability. METHODS AND ANALYSIS: This study will be guided by the methods described in the US Food and Drug Administration Guidance for Industry Patient-reported Outcome Measures. A literature review, cognitive interviews and focus groups with individuals who have experience of working or living with ASDs will be used for item generation. A sample of children and adults with ASD will complete the ACB, in addition to other gold standard measures of concerning behaviour in order to establish the initial psychometric properties of the scale. ETHICS AND DISSEMINATION: This study has received ethical approval from the NHS Research Ethics Committee: London-Camden and King’s Cross (ref: 15/LO/0085). Study findings will be disseminated to healthcare professionals and scientists in the field through publication in peer-reviewed journals and conference presentations.
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19. Tebartz van Elst L, Riedel A, Maier S. {{Autism as a Disorder of Altered Global Functional and Structural Connectivity}}. {Biol Psychiatry}. 2016; 79(8): 626-7.
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20. Tuand K, Stijnen P, Volders K, Declercq J, Nuytens K, Meulemans S, Creemers J. {{Nuclear Localization of the Autism Candidate Gene Neurobeachin and Functional Interaction with the NOTCH1 Intracellular Domain Indicate a Role in Regulating Transcription}}. {PLoS One}. 2016; 11(3): e0151954.
BACKGROUND: Neurobeachin (NBEA) is an autism spectrum disorders (ASD) candidate gene. NBEA deficiency affects regulated secretion, receptor trafficking, synaptic architecture and protein kinase A (PKA)-mediated phosphorylation. NBEA is a large multidomain scaffolding protein. From N- to C-terminus, NBEA has a concanavalin A-like lectin domain flanked by armadillo repeats (ACA), an A-kinase anchoring protein domain that can bind to PKA, a domain of unknown function (DUF1088) and a BEACH domain, preceded by a pleckstrin homology-like domain and followed by WD40 repeats (PBW). Although most of these domains mediate protein-protein interactions, no interaction screen has yet been performed. METHODS: Yeast two-hybrid screens with the ACA and PBW domain modules of NBEA gave a list of interaction partners, which were analyzed for Gene Ontology (GO) enrichment. Neuro-2a cells were used for confocal microscopy and nuclear extraction analysis. NOTCH-mediated transcription was studied with luciferase reporter assays and qRT-PCR, combined with NBEA knockdown or overexpression. RESULTS: Both domain modules showed a GO enrichment for the nucleus. PBW almost exclusively interacted with transcription regulators, while ACA interacted with a number of PKA substrates. NBEA was partially localized in the nucleus of Neuro-2a cells, albeit much less than in the cytoplasm. A nuclear localization signal was found in the DUF1088 domain, which was shown to contribute to the nuclear localization of an EGFP-DPBW fusion protein. Yeast two-hybrid identified the Notch1 intracellular domain as a physical interactor of the PBW domain and a role for NBEA as a negative regulator in Notch-mediated transcription was demonstrated. CONCLUSION: Defining novel interaction partners of conserved NBEA domain modules identified a role for NBEA as transcriptional regulator in the nucleus. The physical interaction of NBEA with NOTCH1 is most relevant for ASD pathogenesis because NOTCH signaling is essential for neural development.
