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Communication, cognitive development and behavior in children with Cornelia de Lange Syndrome (CdLS): preliminary results.

December 23, 2014 - 6:42am
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Communication, cognitive development and behavior in children with Cornelia de Lange Syndrome (CdLS): preliminary results.

Am J Med Genet B Neuropsychiatr Genet. 2014 Apr;165B(3):223-9

Authors: Ajmone PF, Rigamonti C, Dall'Ara F, Monti F, Vizziello P, Milani D, Cereda A, Selicorni A, Costantino A

Abstract
In this study, we present preliminary data on cognitive, behavioral and communication domains of individuals with Cornelia de Lange Syndrome (CdLS), collected through a specific protocol combining direct and indirect tools. Seventeen subjects with CdLS were assessed, 2.5- to 13.4-year-old. Cognitive level of the subjects differed from what previously described in literature, showing more patients with normal or borderline cognitive abilities. We found a relation between severe autistic behavior and comprehension impairments: all children with high CARS score have severe receptive language disability. A correlation was also found between CARS score and ID: high CARS score occurred only in patients with profound levels of ID. Results of this study support the need for a specific assessment protocol tailored for the characteristics of subjects with multiple disabilities, to be able to identify their strengths avoiding the avalanche effect of weaknesses. Most tests on neuropsychological functions have been developed and standardized for typically developing children, and require the integrity of other functions aside the one that is evaluated, determining an underestimation of the level of functioning. This study could be a starting point to develop new models applicable to other genetic syndromes and complex situations; new and wider studies are needed in order to allow a more complete and accurate assessment, thereby ensuring more efficient and family-centered treatment plans.

PMID: 24706566 [PubMed - indexed for MEDLINE]

Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.

December 21, 2014 - 6:14am

Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.

J Med Genet. 2014 Dec 19;

Authors: Spinelli L, Black FM, Berg JN, Eickholt BJ, Leslie NR

Abstract
BACKGROUND: Germline mutations in the phosphatase PTEN are associated with diverse human pathologies, including tumour susceptibility, developmental abnormalities and autism, but any genotype-phenotype relationships are poorly understood.
METHODS: We have studied the functional consequences of seven PTEN mutations identified in patients diagnosed with autism and macrocephaly and five mutations from severe tumour bearing sufferers of PTEN hamartoma tumour syndrome (PHTS).
RESULTS: All seven autism-associated PTEN mutants investigated retained the ability to suppress cellular AKT signalling, although five were highly unstable. Observed effects on AKT also correlated with the ability to suppress soma size and the length and density of dendritic spines in primary neurons. Conversely, all five PTEN mutations from severe cases of PHTS appeared to directly and strongly disrupt the ability to inhibit AKT signalling.
CONCLUSIONS: Our work implies that alleles causing incomplete loss of PTEN function are more commonly linked to autism than to severe PHTS cases.

PMID: 25527629 [PubMed - as supplied by publisher]

A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains.

December 20, 2014 - 8:59am

A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains.

Cell. 2014 Dec 18;159(7):1511-1523

Authors: Irimia M, Weatheritt RJ, Ellis JD, Parikshak NN, Gonatopoulos-Pournatzis T, Babor M, Quesnel-Vallières M, Tapial J, Raj B, O'Hanlon D, Barrios-Rodiles M, Sternberg MJ, Cordes SP, Roth FP, Wrana JL, Geschwind DH, Blencowe BJ

Abstract
Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide "microexons" display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein-interaction networks during neurogenesis, the misregulation of which is linked to autism.

PMID: 25525873 [PubMed - as supplied by publisher]

The human splicing code reveals new insights into the genetic determinants of disease.

December 20, 2014 - 8:59am

The human splicing code reveals new insights into the genetic determinants of disease.

Science. 2014 Dec 18;

Authors: Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, Hua Y, Gueroussov S, Najafabadi HS, Hughes TR, Morris Q, Barash Y, Krainer AR, Jojic N, Scherer SW, Blencowe BJ, Frey BJ

Abstract
To facilitate precision medicine and whole genome annotation, we developed a machine learning technique that scores how strongly genetic variants affect RNA splicing, whose alteration contributes to many diseases. Analysis of over 650,000 intronic and exonic variants reveals widespread patterns of mutation-driven aberrant splicing. Intronic disease mutations alter splicing nine times more often than common variants, and missense exonic disease mutations that least impact protein function are five times more likely to alter splicing than others. Tens of thousands of disease-causing mutations are detected, including those involved in cancers and spinal muscular atrophy. Examination of intronic and exonic variants found using whole genome sequencing of individuals with autism reveals mis-spliced genes with neurodevelopmental phenotypes. Our approach provides evidence for causal variants and should enable new discoveries in precision medicine.

PMID: 25525159 [PubMed - as supplied by publisher]

SG-ADVISER CNV: copy-number variant annotation and interpretation.

December 19, 2014 - 8:43am

SG-ADVISER CNV: copy-number variant annotation and interpretation.

Genet Med. 2014 Dec 18;

Authors: Erikson GA, Deshpande N, Kesavan BG, Torkamani A

Abstract
Purpose:Copy-number variants have been associated with a variety of diseases, especially cancer, autism, schizophrenia, and developmental delay. The majority of clinically relevant events occur de novo, necessitating the interpretation of novel events. In this light, we present the Scripps Genome ADVISER CNV annotation pipeline and Web server, which aims to fill the gap between copy number variant detection and interpretation by performing in-depth annotations and functional predictions for copy number variants.Methods:The Scripps Genome ADVISER CNV suite includes a Web server interface to a high-performance computing environment for calculations of annotations and a table-based user interface that allows for the execution of numerous annotation-based variant filtration strategies and statistics.Results:The annotation results include details regarding location, impact on the coding portion of genes, allele frequency information (including allele frequencies from the Scripps Wellderly cohort), and overlap information with other reference data sets (including ClinVar, DGV, DECIPHER). A summary variant classification is produced (ADVISER score) based on the American College of Medical Genetics and Genomics scoring guidelines. We demonstrate >90% sensitivity/specificity for detection of pathogenic events.Conclusion:Scripps Genome ADVISER CNV is designed to allow users with no prior bioinformatics expertise to manipulate large volumes of copy-number variant data. Scripps Genome ADVISER CNV is available at http://genomics.scripps.edu/ADVISER/.Genet Med advance online publication 18 December 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.180.

PMID: 25521334 [PubMed - as supplied by publisher]

PlexinA polymorphisms mediate the developmental trajectory of human corpus callosum microstructure.

December 19, 2014 - 8:43am

PlexinA polymorphisms mediate the developmental trajectory of human corpus callosum microstructure.

J Hum Genet. 2014 Dec 18;

Authors: Belyk M, Kraft SJ, Brown S

Abstract
PlexinA is a neuronal receptor protein that facilitates axon guidance during embryogenesis. This gene is associated with several neurological disorders including Alzheimer's disease, Parkinson's disease and autism. However, the effect of variants of PlexinA on brain structure remains unclear. We demonstrate that single-nucleotide polymorphisms within the intron and 3'-untranslated region segments of several human PlexinA genes alter the post-natal developmental trajectory of corpus callosum microstructure. This is the first demonstration that PLXNA mediation of neuroanatomical traits can be detected in humans using in vivo neuroimaging techniques. This result should encourage future research that targets specific disease-related polymorphisms and their relevant neural pathways.Journal of Human Genetics advance online publication, 18 December 2014; doi:10.1038/jhg.2014.107.

PMID: 25518740 [PubMed - as supplied by publisher]

Synaptic basis of social dysfunction: a focus on postsynaptic proteins linking group-I mGluRs with AMPARs and NMDARs.

December 19, 2014 - 8:43am
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Synaptic basis of social dysfunction: a focus on postsynaptic proteins linking group-I mGluRs with AMPARs and NMDARs.

Eur J Neurosci. 2014 Apr;39(7):1114-29

Authors: O'Connor EC, Bariselli S, Bellone C

Abstract
Most of us engage in social interactions on a daily basis and the repertoire of social behaviors we acquire during development and later in life are incredibly varied. However, in many neurodevelopmental disorders, including autism spectrum disorders (ASDs), social behavior is severely compromised and indeed this represents a key diagnostic component for such conditions. From genetic association studies, it is increasingly apparent that genes identified as altered in individuals with ASDs often encode synaptic proteins. Moreover, these synaptic proteins typically serve to scaffold group-I metabotropic glutamate receptors (group-I mGluRs) and ionotropic glutamate receptors (iGluRs; AMPARs and NMDARs), or to enable group-I mGluR to iGluR crosstalk via protein synthesis. Here we aim to explore the possibility of a causal link between altered function of such synaptic proteins and impaired social behaviors that feature in neurodevelopmental disorders, such as ASDs. We review the known synaptic function and role in social behaviors of selected post-synaptic structural proteins (Shank, SAPAP and neuroligin) and regulators of protein synthesis (TSC1/2, FMRP and PTEN). While manipulations of proteins involved in group-I mGluR and iGluR scaffolding or crosstalk frequently lead to profound alterations in synaptic function and one or more components of social behavior, the neuronal circuits responsible for impairments in specific social behaviors are often poorly defined. We argue for an improved understanding of the neuronal circuits underlying specific social behaviors to aid the development of new ASD therapies.

PMID: 24712991 [PubMed - indexed for MEDLINE]

Heterogeneity and convergence: the synaptic pathophysiology of autism.

December 19, 2014 - 8:43am
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Heterogeneity and convergence: the synaptic pathophysiology of autism.

Eur J Neurosci. 2014 Apr;39(7):1107-13

Authors: Baudouin SJ

Abstract
Autism is a developmental disorder characterised by a high heterogeneity of clinical diagnoses and genetic associations. This heterogeneity is a challenge for the identification of the pathophysiology of the disease and for the development of new therapeutic strategies. New conceptual approaches are being used to try to challenge this complexity and gene cluster analysis studies suggest that the pathophysiology of autism is associated with a dysregulation of specific cellular mechanisms. This review will present the experimental evidence for a convergence of synaptic pathophysiology between syndromic and non-syndromic forms of autism, grouped under the generic term of autism spectrum disorders. In particular I will highlight the results from genetic mouse models identifying a convergence of dysregulation of the synaptic type I metabotropic glutamate receptor pathway in mouse models for autism spectrum disorders. These results help to build a new conceptual framework for the study of the synaptic phenotype of autism, which is important for the identification of new therapeutic strategies.

PMID: 24712990 [PubMed - indexed for MEDLINE]

NCS-1 deficiency causes anxiety and depressive-like behavior with impaired non-aversive memory in mice.

December 19, 2014 - 8:43am
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NCS-1 deficiency causes anxiety and depressive-like behavior with impaired non-aversive memory in mice.

Physiol Behav. 2014 May 10;130:91-8

Authors: de Rezende VB, Rosa DV, Comim CM, Magno LA, Rodrigues AL, Vidigal P, Jeromin A, Quevedo J, Romano-Silva MA

Abstract
Sensing and regulating intracellular levels of calcium are essential for proper cellular function. In neurons, calcium sensing plays important roles in neuronal plasticity, neurotransmitter release, long-term synapse modification and ion channel activity. Neuronal calcium sensor-1 (NCS-1) is a member of the highly conserved neuronal calcium sensor family. Although NCS-1 has been associated with psychiatric conditions including autism, bipolar disorder and schizophrenia, it is unclear which role NCS-1 plays in behavior. To understand the involvement of NCS-1 in psychiatric conditions, we provided a comprehensive behavioral characterization of NCS-1 knockout (KO) mice. These mice grow and develop normally without apparent abnormalities in comparison to wild type littermates. However, open field showed that NCS-1 deficiency impairs novelty-induced exploratory activity in both KO and heterozygote (HT) mice. Moreover, NCS-1-deficiency also resulted in anxiety- and depressive-like behaviors as demonstrated by elevated plus maze, large open field, forced swim and tail suspension tasks. Furthermore, based on spontaneous object recognition test, non-aversive long-term memory was impaired in NCS-1 KO mice. In contrast, neither social behavior nor a kind of aversive memory was affected under NCS-1 deficiency. These data implicate NCS-1 in exploratory activity, memory and mood-related behaviors, suggesting that NCS-1 gene ablation may result in phenotypic abnormalities associated with neuropsychiatric disorders.

PMID: 24631552 [PubMed - indexed for MEDLINE]

Neuronal nitric oxide synthase and NADPH oxidase interact to affect cognitive, affective, and social behaviors in mice.

December 19, 2014 - 8:43am
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Neuronal nitric oxide synthase and NADPH oxidase interact to affect cognitive, affective, and social behaviors in mice.

Behav Brain Res. 2013 Nov 1;256:320-7

Authors: Walton JC, Selvakumar B, Weil ZM, Snyder SH, Nelson RJ

Abstract
Both nitric oxide (NO) and reactive oxygen species (ROS) generated by nNOS and NADPH oxidase (NOX), respectively, in the brain have been implicated in an array of behaviors ranging from learning and memory to social interactions. Although recent work has elucidated how these separate redox pathways regulate neural function and behavior, the interaction of these two pathways in the regulation of neural function and behavior remains unspecified. Toward this end, the p47phox subunit of NOX, and nNOS were deleted to generate double knockout mice that were used to characterize the behavioral outcomes of concurrent impairment of the NO and ROS pathways in the brain. Mice were tested in a battery of behavioral tasks to evaluate learning and memory, as well as social, affective, and cognitive behaviors. p47phox deletion did not affect depressive-like behavior, whereas nNOS deletion abolished it. Both p47phox and nNOS deletion singly reduced anxiety-like behavior, increased general locomotor activity, impaired spatial learning and memory, and impaired preference for social novelty. Deletion of both genes concurrently had synergistic effects to elevate locomotor activity, impair spatial learning and memory, and disrupt prepulse inhibition of acoustic startle. Although preference for social novelty was impaired in single knockouts, double knockout mice displayed elevated levels of preference for social novelty above that of wild type littermates. These data demonstrate that, depending upon modality, deletion of p47phox and nNOS genes have dissimilar, similar, or additive effects. The current findings provide evidence that the NOX and nNOS redox signaling cascades interact in the brain to affect both cognitive function and social behavior.

PMID: 23948215 [PubMed - indexed for MEDLINE]

Dystroglycan binding to α-neurexin competes with neurexophilin-1 and neuroligin in the brain.

December 18, 2014 - 8:31am
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Dystroglycan binding to α-neurexin competes with neurexophilin-1 and neuroligin in the brain.

J Biol Chem. 2014 Oct 3;289(40):27585-603

Authors: Reissner C, Stahn J, Breuer D, Klose M, Pohlentz G, Mormann M, Missler M

Abstract
α-Neurexins (α-Nrxn) are mostly presynaptic cell surface molecules essential for neurotransmission that are linked to neuro-developmental disorders as autism or schizophrenia. Several interaction partners of α-Nrxn are identified that depend on alternative splicing, including neuroligins (Nlgn) and dystroglycan (αDAG). The trans-synaptic complex with Nlgn1 was extensively characterized and shown to partially mediate α-Nrxn function. However, the interactions of α-Nrxn with αDAG, neurexophilins (Nxph1) and Nlgn2, ligands that occur specifically at inhibitory synapses, are incompletely understood. Using site-directed mutagenesis, we demonstrate the exact binding epitopes of αDAG and Nxph1 on Nrxn1α and show that their binding is mutually exclusive. Identification of an unusual cysteine bridge pattern and complex type glycans in Nxph1 ensure binding to the second laminin/neurexin/sex hormone binding (LNS2) domain of Nrxn1α, but this association does not interfere with Nlgn binding at LNS6. αDAG, in contrast, interacts with both LNS2 and LNS6 domains without inserts in splice sites SS#2 or SS#4 mostly via LARGE (like-acetylglucosaminyltransferase)-dependent glycans attached to the mucin region. Unexpectedly, binding of αDAG at LNS2 prevents interaction of Nlgn at LNS6 with or without splice insert in SS#4, presumably by sterically hindering each other in the u-form conformation of α-Nrxn. Thus, expression of αDAG and Nxph1 together with alternative splicing in Nrxn1α may prevent or facilitate formation of distinct trans-synaptic Nrxn·Nlgn complexes, revealing an unanticipated way to contribute to the identity of synaptic subpopulations.

PMID: 25157101 [PubMed - indexed for MEDLINE]

Parental social responsiveness and risk of autism spectrum disorder in offspring.

December 18, 2014 - 8:31am
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Parental social responsiveness and risk of autism spectrum disorder in offspring.

JAMA Psychiatry. 2014 Aug;71(8):936-42

Authors: Lyall K, Constantino JN, Weisskopf MG, Roberts AL, Ascherio A, Santangelo SL

Abstract
IMPORTANCE: Although autism spectrum disorder (ASD) is known to be heritable, patterns of inheritance of subclinical autistic traits in nonclinical samples are poorly understood.
OBJECTIVE: To examine the familiality of Social Responsiveness Scale (SRS) scores of individuals with and without ASD.
DESIGN, SETTING, AND PARTICIPANTS: We performed a nested case-control study (pilot study: July 1, 2007, through June 30, 2009; full-scale study: September 15, 2008, through September 14, 2012) within a population-based longitudinal cohort. Participants were drawn from the Nurses' Health Study II, a cohort of 116,430 female nurses recruited in 1989. Case participants were index children with reported ASD; control participants were frequency matched by year of birth of case participants among those not reporting ASD. Of 3161 eligible participants, 2144 nurses (67.8%) returned SRS forms for a child and at least 1 parent and were included in these analyses.
EXPOSURE: The SRS scores, as reported by nurse mothers and their spouses, were examined in association with risk of ASD using crude and adjusted logistic regression analyses. The SRS scores of the children were examined in association with SRS scores of the parents using crude and adjusted linear regression analyses stratified by case status.
MAIN OUTCOMES AND MEASURES: Autism spectrum disorder, assessed by maternal report, validated in a subgroup with the Autism Diagnostic Interview-Revised.
RESULTS: A total of 1649 individuals were included in these analyses, including 256 ASD case participants, 1393 control participants, 1233 mothers, and 1614 fathers. Risk of ASD was increased by 85.0% among children whose parents had concordantly elevated SRS scores (odds ratio [OR], 1.85; 95% CI, 1.08-3.16) and by 52.0% when the score of either parent was elevated (OR, 1.52; 95% CI, 1.11-2.06). Elevated scores of the father significantly increased the risk of ASD in the child (OR, 1.94; 95% CI, 1.38-2.71), but no association was seen with elevated scores of the mother. Elevated parent scores significantly increased child scores in controls, corresponding to an increase in 23 points (P < .001).
CONCLUSIONS AND RELEVANCE: These findings support the role of additive genetic influences in concentrating inherited ASD susceptibility in successive generations and the potential role of preferential mating, and suggest that typical variation in parental social functioning can produce clinically significant differences in offspring social traits.

PMID: 25100167 [PubMed - indexed for MEDLINE]

Evidence of reproductive stoppage in families with autism spectrum disorder: a large, population-based cohort study.

December 18, 2014 - 8:31am
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Evidence of reproductive stoppage in families with autism spectrum disorder: a large, population-based cohort study.

JAMA Psychiatry. 2014 Aug;71(8):943-51

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 - indexed for MEDLINE]

Disrupted brain thyroid hormone homeostasis and altered thyroid hormone-dependent brain gene expression in autism spectrum disorders.

December 17, 2014 - 8:00am
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Disrupted brain thyroid hormone homeostasis and altered thyroid hormone-dependent brain gene expression in autism spectrum disorders.

J Physiol Pharmacol. 2014 Apr;65(2):257-72

Authors: Khan A, Harney JW, Zavacki AM, Sajdel-Sulkowska EM

Abstract
The present study examined human postmortem brains for changes consistent with the hypothesis of local brain TH deficiency in autism spectrum disorders (ASD). Brain levels of oxidative stress marker - 3-nitrotyrosine (3-NT), iodothyronine deiodinase type 2(D2) and type 3 (D3), 3',3,5-triiodothyronine (T3) content, mercury content and gene expression levels were analyzed and compared in the several regions of postmortem brains derived from both male and female control and ASD cases, age 4-16 years. We report that some parameters measured, such as D2 are subject to rapid postmortem inactivation, while others that were analyzed showed both brain region- and sex-dependent changes. Levels of 3-NT were overall increased, T3 was decreased in the cortical regions of ASD brains, while mercury levels measured only in the extracortical regions were not different. The expression of several thyroid hormone (TH)-dependent genes was altered in ASD. Data reported here suggest the possibility of brain region-specific disruption of TH homeostasis and gene expression in autism.

PMID: 24781735 [PubMed - indexed for MEDLINE]

Mice over-expressing BDNF in forebrain neurons develop an altered behavioral phenotype with age.

December 17, 2014 - 8:00am
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Mice over-expressing BDNF in forebrain neurons develop an altered behavioral phenotype with age.

Behav Brain Res. 2014 Jul 15;268:222-8

Authors: Weidner KL, Buenaventura DF, Chadman KK

Abstract
Evidence from clinical studies suggests that abnormal activity of brain derived neurotrophic factor (BDNF) contributes to the pathogenesis of autism spectrum disorders (ASDs). A genetically modified line of mice over-expressing a BDNF transgene in forebrain neurons was used to investigate if this mutation leads to changes in behavior consistent with ASD. The mice used in these experiments were behaviorally tested past 5 months of age when spontaneous seizures were evident. These seizures were not observed in age-matched wildtype (WT) mice or younger mice from this transgenic line. The BDNF mice in these experiments weighed less than their WT littermates. The BDNF transgenic (BDNF-tg) mice demonstrated similar levels of sociability in the social approach test. Conversely, the BDNF-tg mice demonstrated less obsessive compulsive-like behavior in the marble burying test, less anxiety-like behavior in the elevated plus maze test, and less depressive-like behavior in the forced swim test. Changes in behavior were found in these older mice that have not been observed in younger mice from this transgenic line, which may be due to the development of seizures as the mice age. These mice do not have an ASD phenotype but may be useful to study adult onset epilepsy.

PMID: 24768643 [PubMed - indexed for MEDLINE]

Increased BDNF expression in fetal brain in the valproic acid model of autism.

December 17, 2014 - 8:00am
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Increased BDNF expression in fetal brain in the valproic acid model of autism.

Mol Cell Neurosci. 2014 Mar;59:57-62

Authors: Almeida LE, Roby CD, Krueger BK

Abstract
Human fetal exposure to valproic acid (VPA), a widely-used anti-epileptic and mood-stabilizing drug, leads to an increased incidence of behavioral and intellectual impairments including autism; VPA administration to pregnant rats and mice at gestational days 12.5 (E12.5) or E13.5 leads to autistic-like symptoms in the offspring and is widely used as an animal model for autism. We report here that this VPA administration protocol transiently increased both BDNF mRNA and BDNF protein levels 5-6-fold in the fetal mouse brain. VPA exposure in utero induced smaller increases in the expression of mRNA encoding the other neurotrophins, NT3 (2.5-fold) and NT4 (2-fold). Expression of the neurotrophin receptors, trkA, trkB and trkC were minimally affected, while levels of the low-affinity neurotrophin receptor, p75(NTR), doubled. Of the nine 5'-untranslated exons of the mouse BDNF gene, only expression of exons I, IV and VI was stimulated by VPA in utero. In light of the well-established role of BDNF in regulating neurogenesis and the laminar fate of postmitotic neurons in the developing cortex, an aberrant increase in BDNF expression in the fetal brain may contribute to VPA-induced cognitive disorders by altering brain development.

PMID: 24480134 [PubMed - indexed for MEDLINE]

MeCP2 is required for activity-dependent refinement of olfactory circuits.

December 17, 2014 - 8:00am
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MeCP2 is required for activity-dependent refinement of olfactory circuits.

Mol Cell Neurosci. 2014 Mar;59:63-75

Authors: Degano AL, Park MJ, Penati J, Li Q, Ronnett GV

Abstract
Methyl CpG binding protein 2 (MeCP2) is a structural chromosomal protein involved in the regulation of gene expression. Alterations in the levels of MeCP2 have been related to neurodevelopmental disorders. Studies in mouse models of MeCP2 deficiency have demonstrated that this protein is important for neuronal maturation, neurite complexity, synaptogenesis, and synaptic plasticity. However, the mechanisms by which MeCP2 dysfunction leads to neurodevelopmental defects, and the role of activity, remain unclear, as most studies examine the adult nervous system, which may obfuscate the primary consequences of MeCP2 mutation. We hypothesize that MeCP2 plays a role during the formation and activity-driven maturation of neural circuits at early postnatal stages. To test this hypothesis, we use the olfactory system as a neurodevelopmental model. This system undergoes postnatal neurogenesis; axons from olfactory neurons form highly stereotyped projections to higher-order neurons, facilitating the detection of possible defects in the establishment of connectivity. In vivo olfactory stimulation paradigms were used to produce physiological synaptic activity in gene-targeted mice in which specific olfactory circuits are visualized. Our results reveal defective postnatal refinement of olfactory circuits in Mecp2 knock out (KO) mice after sensory (odorant) stimulation. This failure in refinement was associated with deficits in the normal responses to odorants, including brain-derived neurotrophic factor (BDNF) production, as well as changes in adhesion molecules known to regulate axonal convergence. The defective refinement observed in Mecp2 KO mice was prevented by daily treatment with ampakine beginning after the first postnatal week. These observations indicate that increasing synaptic activity at early postnatal stage might circumvent the detrimental effect of MeCP2 deficiency on circuitry maturation. The present results provide in vivo evidence in real time for the role of MeCP2 in activity-dependent maturation of olfactory circuitry, with implications for understanding the mechanism of MeCP2 mutations in the development of neural connectivity.

PMID: 24472844 [PubMed - indexed for MEDLINE]

De novo single exon deletion of AUTS2 in a patient with speech and language disorder: a review of disrupted AUTS2 and further evidence for its role in neurodevelopmental disorders.

December 17, 2014 - 8:00am
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De novo single exon deletion of AUTS2 in a patient with speech and language disorder: a review of disrupted AUTS2 and further evidence for its role in neurodevelopmental disorders.

Am J Med Genet A. 2014 Apr;164A(4):958-65

Authors: Amarillo IE, Li WL, Li X, Vilain E, Kantarci S

Abstract
The autism susceptibility candidate 2 (AUTS2) gene is suggested to play a critical role in early brain development, and its association with intellectual disability (ID), autism spectrum disorders, and other neurodevelopmental disorders (NDDs) has recently gained more attention. Genomic rearrangements and copy number variations (CNVs) involving AUTS2 have been implicated in a range of NDDs with or without congenital malformations and dysmorphic features. Here we report a 62 kb de novo deletion encompassing exon 6 of AUTS2 detected by chromosomal microarray analysis (CMA) in a 4.5 year-old female patient with severe speech and language disorder, history of tonic-clonic movements, and pes planus with eversion of the feet. This is one of the smallest de novo intragenic deletions of AUTS2 described in patients with NDDs. We reviewed previously reported small pathogenic CNVs (<300 kb) in 19 cases, and correlated their specific locations within AUTS2 as well as presence of enhancers, regulatory elements, and CpG islands with the clinical findings of these cases and our patient. Our report provides additional insight into the clinical spectrum of AUTS2 disruptions.

PMID: 24459036 [PubMed - indexed for MEDLINE]

MECP2 duplication: possible cause of severe phenotype in females.

December 17, 2014 - 8:00am
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MECP2 duplication: possible cause of severe phenotype in females.

Am J Med Genet A. 2014 Apr;164A(4):1029-34

Authors: Scott Schwoerer J, Laffin J, Haun J, Raca G, Friez MJ, Giampietro PF

Abstract
MECP2 duplication syndrome, originally described in 2005, is an X-linked neurodevelopmental disorder comprising infantile hypotonia, severe to profound intellectual disability, autism or autistic-like features, spasticity, along with a variety of additional features that are not always clinically apparent. The syndrome is due to a duplication (or triplication) of the gene methyl CpG binding protein 2 (MECP2). To date, the disorder has been described almost exclusively in males. Female carriers of the duplication are thought to have no or mild phenotypic features. Recently, a phenotype for females began emerging. We describe a family with ∼290 kb duplication of Xq28 region that includes the MECP2 gene where the proposita and affected family members are female. Twin sisters, presumed identical, presented early with developmental delay, and seizures. Evaluation of the proposita at 25 years of age included microarray comparative genomic hybridization (aCGH) which revealed the MECP2 gene duplication. The same duplication was found in the proposita's sister, who is more severely affected, and the proband's mother who has mild intellectual disability and depression. X-chromosome inactivation studies showed significant skewing in the mother, but was uninformative in the twin sisters. We propose that the MECP2 duplication caused for the phenotype of the proband and her sister. These findings support evidence for varied severity in some females with MECP2 duplications.

PMID: 24458799 [PubMed - indexed for MEDLINE]

Behavioral profile in RASopathies.

December 17, 2014 - 8:00am
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Behavioral profile in RASopathies.

Am J Med Genet A. 2014 Apr;164A(4):934-42

Authors: Alfieri P, Piccini G, Caciolo C, Perrino F, Gambardella ML, Mallardi M, Cesarini L, Leoni C, Leone D, Fossati C, Selicorni A, Digilio MC, Tartaglia M, Mercuri E, Zampino G, Vicari S

Abstract
Here, we describe neurobehavioral features in patients with RASopathies (i.e., Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome), developmental disorders caused by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade. Parents of 70 individuals with a RASopathy were asked to fill out the following questionnaires: Child Behavior Checklist (CBCL), Social Communication Questionnaire version lifetime (SCQ-L), and Modified Checklist for Autism in toddlers (M-CHAT). Data analysis indicated high rates of internalizing (37%) and externalizing problems (31%) on CBCL. Scores over the cut-off were documented in 64% of patients with cardiofaciocutaneous syndrome, 44% with Costello syndrome, and 12% with Noonan syndrome on SCQ-L/M-CHAT. Our findings indicate that mutations promoting dysregulation of the RAS-MAPK cascade mark an increased psychopathological risk and highlight that autistic-like behavior could be underdiagnosed in patients with RASopathies.

PMID: 24458522 [PubMed - indexed for MEDLINE]

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