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The intracellular Na(+)/H(+) exchanger NHE7 effects a Na(+)-coupled, but not K(+)-coupled proton-loading mechanism in endocytosis.

January 6, 2015 - 6:31am
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The intracellular Na(+)/H(+) exchanger NHE7 effects a Na(+)-coupled, but not K(+)-coupled proton-loading mechanism in endocytosis.

Cell Rep. 2014 May 8;7(3):689-96

Authors: Milosavljevic N, Monet M, Léna I, Brau F, Lacas-Gervais S, Feliciangeli S, Counillon L, Poët M

Abstract
Vesicular H(+)-ATPases and ClC-chloride transporters are described to acidify intracellular compartments, which also express the highly conserved Na(+)/H(+) exchangers NHE6, NHE7, and NHE9. Mutations of these exchangers cause autism-spectrum disorders and neurodegeneration. NHE6, NHE7, and NHE9 are hypothesized to exchange cytosolic K(+) for H(+) and alkalinize vesicles, but this notion has remained untested in K(+) because their intracellular localization prevents functional measurements. Using proton-killing techniques, we selected a cell line that expresses wild-type NHE7 at the plasma membrane, enabling measurement of the exchanger's transport parameters. We found that NHE7 transports Li(+) and Na(+), but not K(+), is nonreversible in physiological conditions and is constitutively activated by cytosolic H(+). Therefore, NHE7 acts as a proton-loading transporter rather than a proton leak. NHE7 mediates an acidification of intracellular vesicles that is additive to that of V-ATPases and that accelerates endocytosis. This study reveals an unexpected function for vesicular Na(+)/H(+) exchangers and provides clues for understanding NHE-linked neurological disorders.

PMID: 24767989 [PubMed - indexed for MEDLINE]

Rett syndrome and MeCP2.

January 6, 2015 - 6:31am
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Rett syndrome and MeCP2.

Neuromolecular Med. 2014 Jun;16(2):231-64

Authors: Liyanage VR, Rastegar M

Abstract
Rett syndrome (RTT) is a severe and progressive neurological disorder, which mainly affects young females. Mutations of the methyl-CpG binding protein 2 (MECP2) gene are the most prevalent cause of classical RTT cases. MECP2 mutations or altered expression are also associated with a spectrum of neurodevelopmental disorders such as autism spectrum disorders with recent links to fetal alcohol spectrum disorders. Collectively, MeCP2 relation to these neurodevelopmental disorders highlights the importance of understanding the molecular mechanisms by which MeCP2 impacts brain development, mental conditions, and compromised brain function. Since MECP2 mutations were discovered to be the primary cause of RTT, a significant progress has been made in the MeCP2 research, with respect to the expression, function and regulation of MeCP2 in the brain and its contribution in RTT pathogenesis. To date, there have been intensive efforts in designing effective therapeutic strategies for RTT benefiting from mouse models and cells collected from RTT patients. Despite significant progress in MeCP2 research over the last few decades, there is still a knowledge gap between the in vitro and in vivo research findings and translating these findings into effective therapeutic interventions in human RTT patients. In this review, we will provide a synopsis of Rett syndrome as a severe neurological disorder and will discuss the role of MeCP2 in RTT pathophysiology.

PMID: 24615633 [PubMed - indexed for MEDLINE]

Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.

January 6, 2015 - 6:31am
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Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.

PLoS One. 2014;9(3):e88600

Authors: Huguet G, Nava C, Lemière N, Patin E, Laval G, Ey E, Brice A, Leboyer M, Szepetowski P, Gillberg C, Depienne C, Delorme R, Bourgeron T

Abstract
Inherited and de novo genomic imbalances at chromosome 16p11.2 are associated with autism spectrum disorders (ASD), but the causative genes remain unknown. Among the genes located in this region, PRRT2 codes for a member of the synaptic SNARE complex that allows the release of synaptic vesicles. PRRT2 is a candidate gene for ASD since homozygote mutations are associated with intellectual disability and heterozygote mutations cause benign infantile seizures, paroxysmal dyskinesia, or hemiplegic migraine. Here, we explored the contribution of PRRT2 mutations in ASD by screening its coding part in a large sample of 1578 individuals including 431 individuals with ASD, 186 controls and 961 individuals from the human genome Diversity Panel. We detected 24 nonsynonymous variants, 1 frameshift (A217PfsX8) and 1 in-frame deletion of 6 bp (p.A361_P362del). The frameshift mutation was observed in a control with no history of neurological or psychiatric disorders. The p.A361_P362del was observed in two individuals with autism from sub-Saharan African origin. Overall, the frequency of PRRT2 deleterious variants was not different between individuals with ASD and controls. Remarkably, PRRT2 displays a highly significant excess of nonsynonymous (pN) vs synonymous (pS) mutations in Asia (pN/pS = 4.85) and Europe (pN/pS = 1.62) compared with Africa (pN/pS = 0.26; Asia vs Africa: P = 0.000087; Europe vs Africa P = 0.00035; Europe vs Asia P = P = 0.084). We also showed that whole genome amplification performed through rolling cycle amplification could artificially introduce the A217PfsX8 mutation indicating that this technology should not be performed prior to PRRT2 mutation screening. In summary, our results do not support a role for PRRT2 coding sequence variants in ASD, but provide an ascertainment of its genetic variability in worldwide populations that should help researchers and clinicians to better investigate the role of PRRT2 in human diseases.

PMID: 24594579 [PubMed - indexed for MEDLINE]

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders.

January 6, 2015 - 6:31am
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Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders.

Pharmacogenomics J. 2014 Jun;14(3):295-302

Authors: McCracken JT, Badashova KK, Posey DJ, Aman MG, Scahill L, Tierney E, Arnold LE, Vitiello B, Whelan F, Chuang SZ, Davies M, Shah B, McDougle CJ, Nurmi EL

Abstract
Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability.

PMID: 23856854 [PubMed - indexed for MEDLINE]

Glutamic acid decarboxylase 67 haplodeficiency impairs social behavior in mice.

January 3, 2015 - 7:17am
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Glutamic acid decarboxylase 67 haplodeficiency impairs social behavior in mice.

Genes Brain Behav. 2014 Apr;13(4):439-50

Authors: Sandhu KV, Lang D, Müller B, Nullmeier S, Yanagawa Y, Schwegler H, Stork O

Abstract
Reduced glutamic acid decarboxylase (GAD)67 expression may be causally involved in the development of social withdrawal in neuropsychiatric states such as autism, schizophrenia and bipolar disorder. In this study, we report disturbance of social behavior in male GAD67 haplodeficient mice. GAD67(+/-) mice, compared to GAD67(+/+) littermates, show reduced sociability and decreased intermale aggression, but normal nest building and urine marking behavior, as well as unchanged locomotor activity and anxiety-like behavior. Moreover, the mutants display a reduced sensitivity to both social and non-social odors, indicating a disturbance in the detection and/or processing of socially relevant olfactory stimuli. Indeed, we observed reduced activation of the lateral septum, medial preoptic area, bed nucleus of the stria terminalis, medial and cortical amygdala upon exposure of GAD67(+/-) mice to social interaction paradigm, as indicated by c-Fos immunohistochemistry. These data suggest a disturbance of stimulus processing in the brain circuitry controlling social behavior in GAD67(+/-) mice, which may provide a useful model for studying the impact of a reduced GAD67 expression on alterations of social behavior related to neuropsychiatric disorders.

PMID: 24612522 [PubMed - indexed for MEDLINE]

Genome-wide association analyses of child genotype effects and parent-of-origin effects in specific language impairment.

January 3, 2015 - 7:17am
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Genome-wide association analyses of child genotype effects and parent-of-origin effects in specific language impairment.

Genes Brain Behav. 2014 Apr;13(4):418-29

Authors: Nudel R, Simpson NH, Baird G, O'Hare A, Conti-Ramsden G, Bolton PF, Hennessy ER, SLI Consortium, Ring SM, Davey Smith G, Francks C, Paracchini S, Monaco AP, Fisher SE, Newbury DF

Abstract
Specific language impairment (SLI) is a neurodevelopmental disorder that affects linguistic abilities when development is otherwise normal. We report the results of a genome-wide association study of SLI which included parent-of-origin effects and child genotype effects and used 278 families of language-impaired children. The child genotype effects analysis did not identify significant associations. We found genome-wide significant paternal parent-of-origin effects on chromosome 14q12 (P = 3.74 × 10(-8)) and suggestive maternal parent-of-origin effects on chromosome 5p13 (P = 1.16 × 10(-7)). A subsequent targeted association of six single-nucleotide-polymorphisms (SNPs) on chromosome 5 in 313 language-impaired individuals and their mothers from the ALSPAC cohort replicated the maternal effects, albeit in the opposite direction (P = 0.001); as fathers' genotypes were not available in the ALSPAC study, the replication analysis did not include paternal parent-of-origin effects. The paternally-associated SNP on chromosome 14 yields a non-synonymous coding change within the NOP9 gene. This gene encodes an RNA-binding protein that has been reported to be significantly dysregulated in individuals with schizophrenia. The region of maternal association on chromosome 5 falls between the PTGER4 and DAB2 genes, in a region previously implicated in autism and ADHD. The top SNP in this association locus is a potential expression QTL of ARHGEF19 (also called WGEF) on chromosome 1. Members of this protein family have been implicated in intellectual disability. In summary, this study implicates parent-of-origin effects in language impairment, and adds an interesting new dimension to the emerging picture of shared genetic etiology across various neurodevelopmental disorders.

PMID: 24571439 [PubMed - indexed for MEDLINE]

Autism spectrum disorders in XYY syndrome: two new cases and systematic review of the literature.

January 3, 2015 - 7:17am
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Autism spectrum disorders in XYY syndrome: two new cases and systematic review of the literature.

Eur J Pediatr. 2014 Mar;173(3):277-83

Authors: Margari L, Lamanna AL, Craig F, Simone M, Gentile M

Abstract
UNLABELLED: Abnormalities of the sex chromosomes (47, XXY, 47 XYY, 45,X/46,XY mosaicism) are frequently associated with Autism Spectrum Disorders (ASD), but the male predisposition to these disorders has not been clearly explained. Previously, the role of the X chromosome was considered important in the ASD mainly because autistic symptoms were detected in genetic syndromes involving X chromosome (fragile X syndrome, Rett syndrome, Klinefelter syndrome). Instead, few studies have analyzed the possible role of the Y chromosome in the ASD. This study explores the role of the Y chromosome in ASD through a systematic literature review about the association between ASD and XYY syndrome and a description of two new cases with this association. The literature review considered studies published in peer-reviewed journals, included in the MEDLINE and PubMed databases, that examined the association between ASD and XYY syndrome. Few studies reported the occurrence of ASD in children with XYY karyotype and the majority of them did not reported a well-defined autism diagnostic category associated with an extra Y chromosome, but several clinical conditions that are generically described as language and social impairment.
CONCLUSION: This study underlines the underestimated role of the Y chromosome in ASD, and we postulate that all the ASD associated with the XYY karyotype may presumably fall within mild degree of ASD as in our cases.

PMID: 24464091 [PubMed - indexed for MEDLINE]

Diagnostic exome sequencing identifies two novel IQSEC2 mutations associated with X-linked intellectual disability with seizures: implications for genetic counseling and clinical diagnosis.

January 3, 2015 - 7:17am
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Diagnostic exome sequencing identifies two novel IQSEC2 mutations associated with X-linked intellectual disability with seizures: implications for genetic counseling and clinical diagnosis.

J Genet Couns. 2014 Jun;23(3):289-98

Authors: Gandomi SK, Farwell Gonzalez KD, Parra M, Shahmirzadi L, Mancuso J, Pichurin P, Temme R, Dugan S, Zeng W, Tang S

Abstract
Intellectual disability is a heterogeneous disorder with a wide phenotypic spectrum. Over 1,700 OMIM genes have been associated with this condition, many of which reside on the X-chromosome. The IQSEC2 gene is located on chromosome Xp11.22 and is known to play a significant role in the maintenance and homeostasis of the brain. Mutations in IQSEC2 have been historically associated with nonsyndromic X-linked intellectual disability. Case reports of affected probands show phenotypic overlap with conditions associated with pathogenic MECP2, FOXG1, CDKL5, and MEF2C gene mutations. Affected individuals, however, have also been identified as presenting with additional clinical features including seizures, autistic-behavior, psychiatric problems, and delayed language skills. To our knowledge, only 5 deleterious mutations and 2 intragenic duplications have been previously reported in IQSEC2. Here we report two novel IQSEC2 de novo truncating mutations identified through diagnostic exome sequencing in two severely affected unrelated male probands manifesting developmental delay, seizures, hypotonia, plagiocephaly, and abnormal MRI findings. Overall, diagnostic exome sequencing established a molecular diagnosis for two patients in whom traditional testing methods were uninformative while expanding on the mutational and phenotypic spectrum. In addition, our data suggests that IQSEC2 may be more common than previously appreciated, accounting for approximately 9 % (2/22) of positive findings among patients with seizures referred for diagnostic exome sequencing. Further, these data supports recently published data suggesting that IQSEC2 plays a more significant role in the development of X-linked intellectual disability with seizures than previously anticipated.

PMID: 24306141 [PubMed - indexed for MEDLINE]

Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.

January 1, 2015 - 8:47am

Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.

Mol Syst Biol. 2014;10(12):774

Authors: Li J, Shi M, Ma Z, Zhao S, Euskirchen G, Ziskin J, Urban A, Hallmayer J, Snyder M

Abstract
Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center. RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology.

PMID: 25549968 [PubMed - in process]

Effects of Npas4 deficiency on anxiety, depression-like, cognition and sociability behaviour.

January 1, 2015 - 8:47am

Effects of Npas4 deficiency on anxiety, depression-like, cognition and sociability behaviour.

Behav Brain Res. 2014 Dec 27;

Authors: Jaehne EJ, Klaric TS, Koblar SA, Baune BT, Lewis MD

Abstract
The transcription factor neuronal PAS domain-containing protein 4 (Npas4), which regulates the formation of inhibitory synapses on excitatory neurons, has been suggested as a candidate gene for neurological and psychiatric conditions such as bipolar depression, autism spectrum and cognitive disorders. A mouse model of Npas4 deficiency has been developed to investigate any role in these disorders. Behavioural characterisation of Npas4(-/-), Npas4 (+/-) and Npas4(+/+) mice has been conducted using the open field, elevated zero maze (EZM), Y-maze, sociability test and forced swim test (FST) to investigate a range of behaviours. Npas4(-/-) mice spent more time in the open arm of the EZM than other genotypes, suggesting decreased anxiety-like behaviour. Npas4(+/-) mice, however, were more immobile in the FST than other genotypes, suggesting increased depression-like behaviour, and also showed impaired spatial recognition memory in the Y-maze. There were no differences between genotype in social behaviour. These results suggest that differential levels of Npas4 expression in the brain may regulate anxiety, depression and cognition related disorders.

PMID: 25549857 [PubMed - as supplied by publisher]

An AUTS2-Polycomb complex activates gene expression in the CNS.

January 1, 2015 - 8:47am

An AUTS2-Polycomb complex activates gene expression in the CNS.

Nature. 2014 Dec 18;516(7531):349-54

Authors: Gao Z, Lee P, Stafford JM, von Schimmelmann M, Schaefer A, Reinberg D

Abstract
Naturally occurring variations of Polycomb repressive complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, autism susceptibility candidate 2 (AUTS2). Although AUTS2 is often disrupted in patients with neuronal disorders, the mechanism underlying the pathogenesis is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2-mediated recruitment of P300 leads to gene activation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrated that AUTS2 regulates neuronal gene expression through promoter association. Conditional targeting of Auts2 in the mouse central nervous system (CNS) leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases.

PMID: 25519132 [PubMed - indexed for MEDLINE]

Development of the cerebellum: simple steps to make a 'little brain'.

December 31, 2014 - 8:19am
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Development of the cerebellum: simple steps to make a 'little brain'.

Development. 2014 Nov;141(21):4031-41

Authors: Butts T, Green MJ, Wingate RJ

Abstract
The cerebellum is a pre-eminent model for the study of neurogenesis and circuit assembly. Increasing interest in the cerebellum as a participant in higher cognitive processes and as a locus for a range of disorders and diseases make this simple yet elusive structure an important model in a number of fields. In recent years, our understanding of some of the more familiar aspects of cerebellar growth, such as its territorial allocation and the origin of its various cell types, has undergone major recalibration. Furthermore, owing to its stereotyped circuitry across a range of species, insights from a variety of species have contributed to an increasingly rich picture of how this system develops. Here, we review these recent advances and explore three distinct aspects of cerebellar development - allocation of the cerebellar anlage, the significance of transit amplification and the generation of neuronal diversity - each defined by distinct regulatory mechanisms and each with special significance for health and disease.

PMID: 25336734 [PubMed - indexed for MEDLINE]

Prenatal and perinatal risk factors in a twin study of autism spectrum disorders.

December 31, 2014 - 8:19am
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Prenatal and perinatal risk factors in a twin study of autism spectrum disorders.

J Psychiatr Res. 2014 Jul;54:100-8

Authors: Froehlich-Santino W, Londono Tobon A, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, O'Hara R, Hallmayer J

Abstract
INTRODUCTION: Multiple studies associate prenatal and perinatal complications with increased risks for autism spectrum disorders (ASDs). The objectives of this study were to utilize a twin study design to 1) Investigate whether shared gestational and perinatal factors increase concordance for ASDs in twins, 2) Determine whether individual neonatal factors are associated with the presence of ASDs in twins, and 3) Explore whether associated factors may influence males and females differently.
METHODS: Data from medical records and parent response questionnaires from 194 twin pairs, in which at least one twin had an ASD, were analyzed.
RESULTS: Shared factors including parental age, prenatal use of medications, uterine bleeding, and prematurity did not increase concordance risks for ASDs in twins. Among the individual factors, respiratory distress demonstrated the strongest association with increased risk for ASDs in the group as a whole (OR 2.11, 95% CI 1.27-3.51). Furthermore, respiratory distress (OR 2.29, 95% CI 1.12-4.67) and other markers of hypoxia (OR 1.99, 95% CI 1.04-3.80) were associated with increased risks for ASDs in males, while jaundice was associated with an increased risk for ASDs in females (OR 2.94, 95% CI 1.28-6.74).
CONCLUSIONS: Perinatal factors associated with respiratory distress and other markers of hypoxia appear to increase risk for autism in a subgroup of twins. Future studies examining potential gender differences and additional prenatal, perinatal and postnatal environmental factors are required for elucidating the etiology of ASDs and suggesting new methods for treatment and prevention.

PMID: 24726638 [PubMed - indexed for MEDLINE]

Blood Lead Concentrations in Jamaican Children with and without Autism Spectrum Disorder.

December 30, 2014 - 7:31am

Blood Lead Concentrations in Jamaican Children with and without Autism Spectrum Disorder.

Int J Environ Res Public Health. 2014;12(1):83-105

Authors: Rahbar MH, Samms-Vaughan M, Dickerson AS, Loveland KA, Ardjomand-Hessabi M, Bressler J, Shakespeare-Pellington S, Grove ML, Pearson DA, Boerwinkle E

Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder manifesting by early childhood. Lead is a toxic metal shown to cause neurodevelopmental disorders in children. Several studies have investigated the possible association between exposure to lead and ASD, but their findings are conflicting. Using data from 100 ASD cases (2-8 years of age) and their age- and sex-matched typically developing controls, we investigated the association between blood lead concentrations (BLC) and ASD in Jamaican children. We administered a questionnaire to assess demographic and socioeconomic information as well as exposure to potential lead sources. We used General Linear Models (GLM) to assess the association of BLC with ASD status as well as with sources of exposure to lead. In univariable GLM, we found a significant difference between geometric mean blood lead concentrations of ASD cases and controls (2.25 μg/dL cases vs. 2.73 μg/dL controls, p < 0.05). However, after controlling for potential confounders, there were no significant differences between adjusted geometric mean blood lead concentrations of ASD cases and controls (2.55 μg/dL vs. 2.72 μg/dL, p = 0.64). Our results do not support an association between BLC and ASD in Jamaican children. We have identified significant confounders when assessing an association between ASD and BLC.

PMID: 25546274 [PubMed - as supplied by publisher]

Evidence linking FMR1 mRNA and attentional demands of stepping and postural control in women with the premutation.

December 30, 2014 - 7:31am

Evidence linking FMR1 mRNA and attentional demands of stepping and postural control in women with the premutation.

Neurobiol Aging. 2014 Nov 26;

Authors: Hocking DR, Kraan CM, Godler DE, Bui QM, Li X, Bradshaw JL, Georgiou-Karistianis N, Metcalfe SA, Archibald AD, Turbitt E, Fielding J, Trollor J, Cohen J, Cornish KM

Abstract
Recent studies in young adult females with the fragile X mental retardation 1 (FMR1) gene premutation (PM) have shown subtle but significant impairments in executive control and postural stability. Less is known about the influence of age and FMR1 gene expression on executive control and postural stability in females with the PM. Here, we examined the attentional demands of reactive stepping using a well-validated measure of choice stepping reaction time under dual-task interference. We explored the interrelationships between step initiation times during a concurrent verbal fluency task and specific impairments in executive control previously reported in females with the PM. Our results showed increased dual-task interference on step initiation times and variability in female PM compared with control subjects. In addition, we observed greater choice stepping reaction time dual-task costs above the breakpoint of 81 CGG repeats relative to below this CGG range. Dual-task interference on both reaction time and movement time were significantly predicted by low working memory capacity in female PM carriers. Importantly, we revealed that FMR1 messenger RNA level is the most significant predictor accounting for dual-task stepping variability in both reaction time and movement time in PM females. These findings for the first time provide evidence linking elevated FMR1 messenger RNA levels that have been previously associated with FMR1 RNA toxicity and deficits in cerebellar motor and cognitive networks in a subgroup of at-risk PM women.

PMID: 25541421 [PubMed - as supplied by publisher]

Age-related decreased inhibitory vs. excitatory gene expression in the adult autistic brain.

December 30, 2014 - 7:31am

Age-related decreased inhibitory vs. excitatory gene expression in the adult autistic brain.

Front Neurosci. 2014;8:394

Authors: van de Lagemaat LN, Nijhof B, Bosch DG, Kohansal-Nodehi M, Keerthikumar S, Heimel JA

Abstract
Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by impaired social interaction and communication, and restricted behavior and interests. A disruption in the balance of excitatory and inhibitory neurotransmission has been hypothesized to underlie these disorders. Here we demonstrate that genes of both pathways are affected by ASD, and that gene expression of inhibitory and excitatory genes is altered in the cerebral cortex of adult but not younger autistic individuals. We have developed a measure for the difference in the level of excitation and inhibition based on gene expression and observe that in this measure inhibition is decreased relative to excitation in adult ASD compared to control. This difference was undetectable in young autistic brains. Given that many psychiatric features of autism are already present at an early age, this suggests that the observed imbalance in gene expression is an aging phenomenon in ASD rather than its underlying cause.

PMID: 25538548 [PubMed]

NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development.

December 30, 2014 - 7:31am
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NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development.

Genes Dev. 2014 Nov 1;28(21):2407-20

Authors: Sanchez-Ortiz E, Cho W, Nazarenko I, Mo W, Chen J, Parada LF

Abstract
Cerebellar development is regulated by a coordinated spatiotemporal interplay between granule neuron progenitors (GNPs), Purkinje neurons, and glia. Abnormal development can trigger motor deficits, and more recent data indicate important roles in aspects of memory, behavior, and autism spectrum disorders (ASDs). Germline mutation in the NF1 tumor suppressor gene underlies Neurofibromatosis type 1, a complex disease that enhances susceptibility to certain cancers and neurological disorders, including intellectual deficits and ASD. The NF1 gene encodes for neurofibromin, a RAS GTPase-activating protein, and thus negatively regulates the RAS signaling pathway. Here, using mouse models to direct conditional NF1 ablation in either embryonic cerebellar progenitors or neonatal GNPs, we show that neurofibromin is required for appropriate development of cerebellar folia layering and structure. Remarkably, neonatal administration of inhibitors of the ERK pathway reversed the morphological defects. Thus, our findings establish a critical cell-autonomous role for the NF1-RAS-ERK pathway in the appropriate regulation of cerebellar development and provide a basis for using neonatal ERK inhibitor-based therapies to treat NF1-induced cerebellar disorders.

PMID: 25367036 [PubMed - indexed for MEDLINE]

Resolving genomic disorder-associated breakpoints within segmental DNA duplications using massively parallel sequencing.

December 30, 2014 - 7:31am
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Resolving genomic disorder-associated breakpoints within segmental DNA duplications using massively parallel sequencing.

Nat Protoc. 2014;9(6):1496-513

Authors: Nuttle X, Itsara A, Shendure J, Eichler EE

Abstract
The most common recurrent copy-number variants associated with autism, developmental delay and epilepsy are flanked by segmental duplications. Complete genetic characterization of these events is challenging because their breakpoints often occur within high-identity, copy-number polymorphic paralogous sequences that cannot be specifically assayed using hybridization-based methods. Here we provide a protocol for breakpoint resolution with sequence-level precision. Massively parallel sequencing is performed on libraries generated from haplotype-resolved chromosomes, genomic DNA or molecular inversion probe (MIP)-captured breakpoint-informative regions harboring paralog-distinguishing variants. Quantification of sequencing depth over informative sites enables breakpoint localization, typically within several kilobases to tens of kilobases. Depending on the approach used, the sequencing platform, and the accuracy and completeness of the reference genome sequence, this protocol takes from a few days to several months to complete. Once established for a specific genomic disorder, it is possible to process thousands of DNA samples within as little as 3-4 weeks.

PMID: 24874815 [PubMed - indexed for MEDLINE]

KCTD10 is critical for heart and blood vessel development of zebrafish.

December 30, 2014 - 7:31am
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KCTD10 is critical for heart and blood vessel development of zebrafish.

Acta Biochim Biophys Sin (Shanghai). 2014 May;46(5):377-86

Authors: Hu X, Gan S, Xie G, Li L, Chen C, Ding X, Han M, Xiang S, Zhang J

Abstract
KCTD10 is a member of the PDIP1 family, which is highly conserved during evolution, sharing a lot of similarities among human, mouse, and zebrafish. Recently, zebrafish KCTD13 has been identified to play an important role in the early development of brain and autism. However, the specific function of KCTD10 remains to be elucidated. In this study, experiments were carried out to determine the expression pattern of zebrafish KCTD10 mRNA during embryonic development. It was found that KCTD10 is a maternal gene and KCTD10 is of great importance in the shaping of heart and blood vessels. Our data provide direct clues that knockdown of KCTD10 resulted in severe pericardial edema and loss of heart formation indicated by morphological observation and crucial heart markers like amhc, vmhc, and cmlc2. The heart defect caused by KCTD10 is linked to RhoA and PCNA. Flk-1 staining revealed that intersomitic vessels were lost in the trunk, although angioblasts could migrate to the midline. These findings could be helpful to better understand the determinants responsible for the heart and blood vessel defects.

PMID: 24705121 [PubMed - indexed for MEDLINE]

High content image analysis identifies novel regulators of synaptogenesis in a high-throughput RNAi screen of primary neurons.

December 30, 2014 - 7:31am
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High content image analysis identifies novel regulators of synaptogenesis in a high-throughput RNAi screen of primary neurons.

PLoS One. 2014;9(3):e91744

Authors: Nieland TJ, Logan DJ, Saulnier J, Lam D, Johnson C, Root DE, Carpenter AE, Sabatini BL

Abstract
The formation of synapses, the specialized points of chemical communication between neurons, is a highly regulated developmental process fundamental to establishing normal brain circuitry. Perturbations of synapse formation and function causally contribute to human developmental and degenerative neuropsychiatric disorders, such as Alzheimer's disease, intellectual disability, and autism spectrum disorders. Many genes controlling synaptogenesis have been identified, but lack of facile experimental systems has made systematic discovery of regulators of synaptogenesis challenging. Thus, we created a high-throughput platform to study excitatory and inhibitory synapse development in primary neuronal cultures and used a lentiviral RNA interference library to identify novel regulators of synapse formation. This methodology is broadly applicable for high-throughput screening of genes and drugs that may rescue or improve synaptic dysfunction associated with cognitive function and neurological disorders.

PMID: 24633176 [PubMed - indexed for MEDLINE]

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