1. Choi J, Ababon MR, Matteson PG, Millonig JH. {{Cut-like Homeobox1 and Nuclear Factor I/B Mediate ENGRAILED2 Autism Spectrum Disorder-associated haplotype function}}. {Hum Mol Genet};2011 (Dec 16)
Both common and rare variants contribute to Autism Spectrum Disorder (ASD) risk, but few variants have been established as functional. Previously we demonstrated that an intronic haplotype (rs1861972-rs1861973 A-C) in the homeobox transcription factor ENGRAILED2 (EN2) is significantly associated with ASD. Positive association has also been reported in six additional datasets, suggesting EN2 is an ASD susceptibility gene. Additional support for this possibility requires the identification of functional variants that affect EN2 regulation or activity. In the present study, we demonstrate that the A-C haplotype is a transcriptional activator. Luciferase (luc) assays in mouse neuronal cultures determined that the A-C haplotype increases expression levels (50%, p<0.01, 24hrs; 250%, p<0.0001, 72hrs). Mutational analysis indicates that the A-C haplotype activator function requires both associated A and C alleles. A minimal 202bp element is sufficient for function and also specifically binds a protein complex. Mass spectrometry identified these proteins as the transcription factors, Cut-like homeobox 1 (Cux1) and Nuclear factor I/B (Nfib). Subsequent antibody supershifts and chromatin immunoprecipitations demonstrated human CUX1 and NFIB bind the A-C haplotype. Co-transfection and knock-down experiments determined that both CUX1 and NFIB are required for the A-C haplotype activator function. These data demonstrate that the ASD-associated A-C haplotype is a transcriptional activator, and both CUX1 and NFIB mediate this activity. These results provide biochemical evidence that the ASD-associated A-C haplotype is functional, further supporting EN2 as an ASD susceptibility gene.
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2. Fernandez TV, Sanders SJ, Yurkiewicz IR, Ercan-Sencicek AG, Kim YS, Fishman DO, Raubeson MJ, Song Y, Yasuno K, Ho WS, Bilguvar K, Glessner J, Chu SH, Leckman JF, King RA, Gilbert DL, Heiman GA, Tischfield JA, Hoekstra PJ, Devlin B, Hakonarson H, Mane SM, Gunel M, State MW. {{Rare Copy Number Variants in Tourette Syndrome Disrupt Genes in Histaminergic Pathways and Overlap with Autism}}. {Biol Psychiatry};2011 (Dec 12)
BACKGROUND: Studies of copy number variation (CNV) have characterized loci and molecular pathways in a range of neuropsychiatric conditions. We analyzed rare CNVs in Tourette syndrome (TS) to identify novel risk regions and relevant pathways, to evaluate burden of structural variation in cases versus controls, and to assess overlap of identified variations with those in other neuropsychiatric syndromes. METHODS: We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370 K to 1 M probe arrays, and genotyping data were used to match cases and controls for ancestry. CNVs present in < 1% of the population were evaluated. RESULTS: While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (subtypes 1 and 2) signaling pathways (p = 5.8 x 10(-4) – 1.6 x 10(-2)), as well as axon guidance, cell adhesion, nervous system development, and synaptic structure and function processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders but not intellectual disability or schizophrenia. Three large, likely pathogenic, de novo events were identified, including one disrupting multiple gamma-aminobutyric acid receptor genes. CONCLUSIONS: We identify further evidence supporting recent findings regarding the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorders.
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3. Larson MJ, South M, Clayson PE, Clawson A. {{Cognitive control and conflict adaptation in youth with high-functioning autism}}. {J Child Psychol Psychiatry};2011 (Dec 16)
Background: Youth diagnosed with autism spectrum disorders (ASD) often show deficits in cognitive control processes, potentially contributing to characteristic difficulties monitoring and regulating behavior. Modification of performance following conflict can be measured by examining conflict adaptation, the adjustment of cognitive resources based on previous-trial conflict. The electrophysiological correlates of these processes can be measured using the N2, a stimulus-locked component of the event-related potential (ERP). Methods: High-density ERPs and behavioral data [i.e. response times (RTs) and error rates] were acquired while 28 youth with ASD and 36 typically developing controls completed a modified Eriksen flanker task. Results: Behaviorally, groups showed similar conflict adaptation effects; youth with ASD showed larger RT slowing on switch trials. For electrophysiology, controls demonstrated larger N2 amplitudes for incongruent (high-conflict) trials following congruent (low-conflict) trials than for incongruent trials following incongruent trials. Importantly, youth with ASD showed no such differences in N2 amplitude based on previous-trial conflict. Conclusions: Lack of electrophysiological conflict adaptation effects in youth with ASD indicates irregular neural processing associated with conflict adaptation. Individuals with ASD show declines in level of conflict evaluation and adaptation. Future research is necessary to accurately characterize and understand the behavioral implications of these cognitive control deficits relative to diagnostic severity, anxiety, and personality.
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4. Lee BK, Gardner RM, Dal H, Svensson A, Galanti MR, Rai D, Dalman C, Magnusson C. {{Brief Report: Maternal Smoking During Pregnancy and Autism Spectrum Disorders}}. {J Autism Dev Disord};2011 (Dec 16)
Prenatal exposure to tobacco smoke is suggested as a potential risk factor for autism spectrum disorders (ASD). Previous epidemiological studies of this topic have yielded mixed findings. We performed a case-control study of 3,958 ASD cases and 38,983 controls nested in a large register-based cohort in Sweden. ASD case status was measured using a multisource case ascertainment system. In adjusted results, we found that maternal smoking during pregnancy is not associated with increased risk of ASD regardless of presence or absence of comorbid intellectual disability. Apparent associations were attributable to confounding by sociodemographic characteristics of parents such as education, income, and occupation.
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5. Puleo CM, Schmeidler J, Reichenberg A, Kolevzon A, Soorya LV, Buxbaum JD, Silverman JM. {{Advancing paternal age and simplex autism}}. {Autism};2011 (Dec 16)
De novo events appear more common in female and simplex autism spectrum disorder (ASD) cases and may underlie greater ASD risk in older fathers’ offspring. This study examined whether advancing paternal age predicts an increase in simplex (n = 90) versus multiplex ASD cases (n = 587) in 677 participants (340 families). Whether or not controlling for maternal age, results support a significant interaction of linear paternal age and sex of the child on simplex family type. Female ASD cases were significantly more likely to be simplex as paternal age increased, but the increase for males was not significant. Findings suggest that ASD arising from non-familial, de novo events may be far less prominent in males than in females, even if more prevalent in males, due to the substantially larger number of male cases attributable to other, more strongly male-biased risk factors.
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6. van Haasteren J. {{Autism: Social norms depend on what is typical}}. {Nature};2011 (Dec 15);480(7377):321.
