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Familial KANK1 deletion that does not follow expected imprinting pattern.

January 3, 2014 - 7:55am
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Familial KANK1 deletion that does not follow expected imprinting pattern.

Eur J Med Genet. 2013 May;56(5):256-9

Authors: Vanzo RJ, Martin MM, Sdano MR, South ST

Abstract
Deletion of the KANK1 gene (also called ANKRD15), located at chromosome position 9p24.3, has been associated with neurodevelopmental disease including congenital cerebral palsy, hypotonia, quadriplegia, and intellectual disability in a four-generation family. The inheritance pattern in this family was suggested to be maternal imprinting, as all affected individuals inherited the deletion from their fathers and monoallelic protein expression was observed. We present a family in which the proband's phenotype, including autism spectrum disorder, motor delay, and intellectual disability, is consistent with this previous report of KANK1 deletions. However, a paternally inherited deletion in the proband's unaffected sibling did not support maternal imprinting. This family raises consideration of further complexity of the KANK1 locus, including variable expressivity, incomplete penetrance, and the additive effects of additional genomic variants or the potential benign nature of inherited copy number variations (CNVs). However, when considered with the previous publication, our case also suggests that KANK1 may be subject to random monoallelic expression as a possible mode of inheritance. It is also important to consider that KANK1 has two alternately spliced transcripts, A and B. These have differential tissue expression and thus potentially differential clinical significance. Based upon cases in the literature, the present case, and information in the Database of Genomic Variants, it is possible that only aberrations of variant A contribute to neurodevelopmental disease. The familial deletion in this present case does not support maternal imprinting as an inheritance pattern. We suggest that other inheritance patterns and caveats should be considered when evaluating KANK1 deletions, which may become increasingly recognized through whole genome microarray testing, whole genome sequencing, and whole exome sequencing techniques.

PMID: 23454270 [PubMed - indexed for MEDLINE]

Association of autism with induced or augmented childbirth - Authors' Response.

January 2, 2014 - 7:30am

Association of autism with induced or augmented childbirth - Authors' Response.

Am J Obstet Gynecol. 2013 Dec 28;

Authors: Miranda ML, Anthopolos R, Gregory SG

PMID: 24380745 [PubMed - as supplied by publisher]

iPSC-derived neurons as a higher-throughput readout for autism: promises and pitfalls.

January 1, 2014 - 7:18am
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iPSC-derived neurons as a higher-throughput readout for autism: promises and pitfalls.

Trends Mol Med. 2013 Dec 24;

Authors: Prilutsky D, Palmer NP, Smedemark-Margulies N, Schlaeger TM, Margulies DM, Kohane IS

Abstract
The elucidation of disease etiologies and establishment of robust, scalable, high-throughput screening assays for autism spectrum disorders (ASDs) have been impeded by both inaccessibility of disease-relevant neuronal tissue and the genetic heterogeneity of the disorder. Neuronal cells derived from induced pluripotent stem cells (iPSCs) from autism patients may circumvent these obstacles and serve as relevant cell models. To date, derived cells are characterized and screened by assessing their neuronal phenotypes. These characterizations are often etiology-specific or lack reproducibility and stability. In this review, we present an overview of efforts to study iPSC-derived neurons as a model for autism, and we explore the plausibility of gene expression profiling as a reproducible and stable disease marker.

PMID: 24374161 [PubMed - as supplied by publisher]

Overexpression of calcium-activated potassium channels underlies cortical dysfunction in a model of PTEN-associated autism.

January 1, 2014 - 7:18am
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Overexpression of calcium-activated potassium channels underlies cortical dysfunction in a model of PTEN-associated autism.

Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18297-302

Authors: Garcia-Junco-Clemente P, Chow DK, Tring E, Lazaro MT, Trachtenberg JT, Golshani P

Abstract
De novo phosphatase and tensin homolog on chromosome ten (PTEN) mutations are a cause of sporadic autism. How single-copy loss of PTEN alters neural function is not understood. Here we report that Pten haploinsufficiency increases the expression of small-conductance calcium-activated potassium channels. The resultant augmentation of this conductance increases the amplitude of the afterspike hyperpolarization, causing a decrease in intrinsic excitability. In vivo, this change in intrinsic excitability reduces evoked firing rates of cortical pyramidal neurons but does not alter receptive field tuning. The decreased in vivo firing rate is not associated with deficits in the dendritic integration of synaptic input or with changes in dendritic complexity. These findings identify calcium-activated potassium channelopathy as a cause of cortical dysfunction in the PTEN model of autism and provide potential molecular therapeutic targets.

PMID: 24145404 [PubMed - indexed for MEDLINE]

[Drug development targeting synaptic molecules - autism mouse models as an example].

January 1, 2014 - 7:18am
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[Drug development targeting synaptic molecules - autism mouse models as an example].

Nihon Yakurigaku Zasshi. 2013 Sep;142(3):116-21

Authors: Sakurai T

PMID: 24025492 [PubMed - indexed for MEDLINE]

Characterizing social behavior in genetically targeted mouse models of brain disorders.

January 1, 2014 - 7:18am
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Characterizing social behavior in genetically targeted mouse models of brain disorders.

Methods Mol Biol. 2013;1017:95-104

Authors: Burrows EL, Hannan AJ

Abstract
Fragile X syndrome, the leading inherited cause of mental retardation and autism spectrum disorders worldwide, is caused by a tandem repeat expansion in the FMR1 (fragile X mental retardation 1) gene. It presents with a distinct behavioral phenotype which overlaps significantly with that of autism. Emerging evidence suggests that tandem repeat polymorphisms (TRPs) might also play a key role in modulating disease susceptibility for a range of common polygenic disorders, including the broader autism spectrum of disorders (ASD) and other forms of psychiatric illness such as schizophrenia, depression, and bipolar disorder [1]. In order to understand how TRPs and associated gene mutations mediate pathogenesis, various mouse models have been generated. A crucial step in such functional genomics is high-quality behavioral and cognitive phenotyping. This chapter presents a basic behavioral battery for standardized tests for assaying social phenotypes in mouse models of brain disorders, with a focus on aggression.

PMID: 23719910 [PubMed - indexed for MEDLINE]

Empathizing, systemizing, and autistic traits: latent structure in individuals with autism, their parents, and general population controls.

January 1, 2014 - 7:18am
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Empathizing, systemizing, and autistic traits: latent structure in individuals with autism, their parents, and general population controls.

J Abnorm Psychol. 2013 May;122(2):600-9

Authors: Grove R, Baillie A, Allison C, Baron-Cohen S, Hoekstra RA

Abstract
The search for genes involved in autism spectrum conditions (ASC) may have been hindered by the assumption that the different symptoms that define the condition can be attributed to the same causal mechanism. Instead the social and nonsocial aspects of ASC may have distinct causes at genetic, cognitive, and neural levels. It has been posited that the core features of ASC can be explained by a deficit in empathizing alongside intact or superior systemizing; the drive to understand and derive rules about a system. First-degree relatives also show some mild manifestations that parallel the defining features of ASC, termed the broader autism phenotype. Factor analyses were conducted to assess whether the latent structure of empathizing, systemizing, and autistic traits differs across samples with a high (individuals on the spectrum), medium (first-degree relatives) or low (general population controls) genetic vulnerability to autism. Results highlighted a two-factor model, confirming an empathizing and a systemizing factor. The relationship between these two factors was significantly stronger in first-degree relatives and the autism group compared with controls. The same model provided the best fit among the three groups, suggesting a similar latent structure irrespective of genetic vulnerability. However, results also suggest that although these traits are relatively independent in the general population, they are substantially correlated in individuals with ASC and their parents. This implies that there is substantially more overlap between systemizing and empathizing among individuals with an increased genetic liability to autism. This has potential implications for the genetic, environmental, and cognitive explanations of autism spectrum conditions.

PMID: 23713510 [PubMed - indexed for MEDLINE]

Deficiency of the cyclin-dependent kinase inhibitor, CDKN1B, results in overgrowth and neurodevelopmental delay.

January 1, 2014 - 7:18am
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Deficiency of the cyclin-dependent kinase inhibitor, CDKN1B, results in overgrowth and neurodevelopmental delay.

Hum Mutat. 2013 Jun;34(6):864-8

Authors: Grey W, Izatt L, Sahraoui W, Ng YM, Ogilvie C, Hulse A, Tse E, Holic R, Yu V

Abstract
Germline mutations in the cyclin-dependent kinase inhibitor, CDKN1B, have been described in patients with multiple endocrine neoplasia (MEN), a cancer predisposition syndrome with adult onset neoplasia and no additional phenotypes. Here, we describe the first human case of CDKN1B deficiency, which recapitulates features of the murine CDKN1B knockout mouse model, including gigantism and neurodevelopmental defects. Decreased mRNA and protein expression of CDKN1B were confirmed in the proband's peripheral blood, which is not seen in MEN syndrome patients. We ascribed the decreased protein level to a maternally derived deletion on chromosome 12p13 encompassing the CDKN1B locus (which reduced mRNA expression) and a de novo allelic variant (c.-73G>A) in the CDKN1B promoter (which reduced protein translation). We propose a recessive model where decreased dosage of CDKN1B during development in humans results in a neuronal phenotype akin to that described in mice, placing CDKN1B as a candidate gene involved in developmental delay.

PMID: 23505216 [PubMed - indexed for MEDLINE]

Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity.

January 1, 2014 - 7:18am
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Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity.

Hum Mol Genet. 2013 Jun 1;22(11):2186-99

Authors: Lignani G, Raimondi A, Ferrea E, Rocchi A, Paonessa F, Cesca F, Orlando M, Tkatch T, Valtorta F, Cossette P, Baldelli P, Benfenati F

Abstract
Synapsin I (SynI) is a synaptic vesicle (SV) phosphoprotein playing multiple roles in synaptic transmission and plasticity by differentially affecting crucial steps of SV trafficking in excitatory and inhibitory synapses. SynI knockout (KO) mice are epileptic, and nonsense and missense mutations in the human SYN1 gene have a causal role in idiopathic epilepsy and autism. To get insights into the mechanisms of epileptogenesis linked to SYN1 mutations, we analyzed the effects of the recently identified Q555X mutation on neurotransmitter release dynamics and short-term plasticity (STP) in excitatory and inhibitory synapses. We used patch-clamp electrophysiology coupled to electron microscopy and multi-electrode arrays to dissect synaptic transmission of primary SynI KO hippocampal neurons in which the human wild-type and mutant SynI were expressed by lentiviral transduction. A parallel decrease in the SV readily releasable pool in inhibitory synapses and in the release probability in excitatory synapses caused a marked reduction in the evoked synchronous release. This effect was accompanied by an increase in asynchronous release that was much more intense in excitatory synapses and associated with an increased total charge transfer. Q555X-hSynI induced larger facilitation and post-tetanic potentiation in excitatory synapses and stronger depression after long trains in inhibitory synapses. These changes were associated with higher network excitability and firing/bursting activity. Our data indicate that imbalances in STP and release dynamics of inhibitory and excitatory synapses trigger network hyperexcitability potentially leading to epilepsy/autism manifestations.

PMID: 23406870 [PubMed - indexed for MEDLINE]

Evidence of a distinct behavioral phenotype in young boys with fragile X syndrome and autism.

January 1, 2014 - 7:18am
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Evidence of a distinct behavioral phenotype in young boys with fragile X syndrome and autism.

J Am Acad Child Adolesc Psychiatry. 2012 Dec;51(12):1324-32

Authors: Wolff JJ, Bodfish JW, Hazlett HC, Lightbody AA, Reiss AL, Piven J

Abstract
OBJECTIVE: How does the behavioral expression of autism in fragile X syndrome (FXS + Aut) compare with idiopathic autism (iAut)? Although social impairments and restricted, repetitive behaviors are common to these variants of autism, closer examination of these symptom domains may reveal meaningful similarities and differences. To this end, the specific behaviors comprising the social and repetitive behavioral domains in young children with FXS + Aut and iAut were profiled.
METHOD: Twenty-three male subjects 3 to 5 years old with FXS + Aut were matched by age to a group of 38 boys with iAut. Repetitive behavior was assessed using the Repetitive Behavior Scales-Revised. Social behavior was evaluated using Autism Diagnostic Observation Schedule social item severity scores.
RESULTS: Rates of stereotypy, self-injury, and sameness behaviors did not differ between groups, whereas compulsive and ritual behavior scores were significantly lower for subjects with FXS + Aut compared with those with iAut. Those with FXS + Aut scored significantly lower (less severe) than the iAut group on five Autism Diagnostic Observation Schedule measurements of social behavior: gaze integration, quality of social overtures, social smile, facial expressions, and response to joint attention.
CONCLUSIONS: The behavioral phenotype of FXS + Aut and iAut are most similar with respect to lower-order (motoric) restricted, repetitive behaviors and social approach, but differ in more complex forms of restricted, repetitive behaviors and some social response behaviors. These findings highlight the phenotypic heterogeneity of autism overall and its unique presentation in an etiologically distinct condition.

PMID: 23200289 [PubMed - indexed for MEDLINE]

Monozygotic twins discordant for submicroscopic chromosomal anomalies in 2p25.3 region detected by array CGH.

January 1, 2014 - 7:18am
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Monozygotic twins discordant for submicroscopic chromosomal anomalies in 2p25.3 region detected by array CGH.

Clin Genet. 2013 Jul;84(1):31-6

Authors: Rio M, Royer G, Gobin S, de Blois MC, Ozilou C, Bernheim A, Nizon M, Munnich A, Bonnefont JP, Romana S, Vekemans M, Turleau C, Malan V

Abstract
Although discordant phenotypes in monozygotic twins with developmental disorder are not an exception, underlying genetic discordance is rarely reported. Here, we report on the clinical and cytogenetic details of 4-year-old female monozygotic twins with discordant phenotypes. Twin 1 exhibited global developmental delay, overweight and hyperactivity. Twin 2 had an autistic spectrum disorder. Molecular karyotyping in twin 1 identified a 2p25.3 deletion, further confirmed by Fluorescence in situ hybridization (FISH) analysis on leukocytes. Interestingly, array comparative genomic hybridization was normal in twin 2 but FISH analysis using the same probe as twin 1 showed mosaicism with one-third of cells with a 2p25.3 deletion, one-third of cells with a 2p25.3 duplication, and one-third of normal cells. Genotyping with microsatellite markers confirmed the monozygosity of the twins. We propose that the chromosome imbalance may be due to a mitotic non-allelic recombination occurring during blastomeric divisions of a normal zygote. Such event will result in three distinct cell populations, whose proportion in each embryo formed after separation from the zygote may differ, leading to discordant chromosomal anomalies between twins. We also discuss that the MYTL1L and the SNTG2 genes within the reported region could probably relate to the phenotypic discordance of the monozygotic twins.

PMID: 23061379 [PubMed - indexed for MEDLINE]

The role of microbiome in central nervous system disorders.

December 29, 2013 - 6:58am
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The role of microbiome in central nervous system disorders.

Brain Behav Immun. 2013 Dec 23;

Authors: Wang Y, Kasper LH

Abstract
Mammals live in a co-evolutionary association with the plethora of microorganisms that reside at a variety of tissue microenvironments. The microbiome represents the collective genomes of these co-existing microorganisms, which is shaped by host factors such as genetics and nutrients but in turn is able to influence host biology in health and disease. Niche-specific microbiome, prominently the gut microbiome, has the capacity to effect both local and distal sites within the host. The gut microbiome has played a crucial role in the bidirectional gut-brain axis that integrates the gut and central nervous system (CNS) activities, and thus the concept of microbiome-gut-brain axis is emerging. Studies are revealing how diverse forms of neuro-immune and neuro-psychiatric disorders are correlated with or modulated by variations of microbiome, microbiota-derived products and exogenous antibiotics and probiotics. The microbiome poises the peripheral immune homeostasis and predisposes host susceptibility to CNS autoimmune diseases such as multiple sclerosis. Neural, endocrine and metabolic mechanisms are also critical mediators of the microbiome-CNS signaling, which are more involved in neuro-psychiatric disorders such as autism, depression, anxiety, stress. Research on the role of microbiome in CNS disorders deepens our academic knowledge about host-microbiome commensalism in central regulation and in practicality, holds conceivable promise for developing novel prognostic and therapeutic avenues for CNS disorders.

PMID: 24370461 [PubMed - as supplied by publisher]

Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models.

December 29, 2013 - 6:58am
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Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models.

PLoS One. 2013;8(3):e59685

Authors: Zeng L, Zhang P, Shi L, Yamamoto V, Lu W, Wang K

Abstract
Exonic deletions in NRXN1 have been associated with several neurodevelopmental disorders, including autism, schizophrenia and developmental delay. However, the molecular mechanism by which NRXN1 deletions impact neurodevelopment remains unclear. Here we used human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) as models to investigate the functional impacts of NRXN1 knockdown. We first generated hiPSCs from skin fibroblasts and differentiated them into neural stem cells (NSCs). We reduced NRXN1 expression in NSCs via a controlled shRNAmir-based knockdown system during differentiation, and monitored the transcriptome alteration by RNA-Seq and quantitative PCR at several time points. Interestingly, half reduction of NRXN1 expression resulted in changes of expression levels for the cell adhesion pathway (20 genes, P = 2.8×10(-6)) and neuron differentiation pathway (13 genes, P = 2.1×10(-4)), implicating that single-gene perturbation can impact biological networks important for neurodevelopment. Furthermore, astrocyte marker GFAP was significantly reduced in a time dependent manner that correlated with NRXN1 reduction. This observation was reproduced in both hiPSCs and hESCs. In summary, based on in vitro models, NRXN1 deletions impact several biological processes during neurodevelopment, including synaptic adhesion and neuron differentiation. Our study highlights the utility of stem cell models in understanding the functional roles of copy number variations (CNVs) in conferring susceptibility to neurodevelopmental diseases.

PMID: 23536886 [PubMed - indexed for MEDLINE]

Monoamine oxidase A and A/B knockout mice display autistic-like features.

December 29, 2013 - 6:58am
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Monoamine oxidase A and A/B knockout mice display autistic-like features.

Int J Neuropsychopharmacol. 2013 May;16(4):869-88

Authors: Bortolato M, Godar SC, Alzghoul L, Zhang J, Darling RD, Simpson KL, Bini V, Chen K, Wellman CL, Lin RC, Shih JC

Abstract
Converging lines of evidence show that a sizable subset of autism-spectrum disorders (ASDs) is characterized by increased blood levels of serotonin (5-hydroxytryptamine, 5-HT), yet the mechanistic link between these two phenomena remains unclear. The enzymatic degradation of brain 5-HT is mainly mediated by monoamine oxidase (MAO)A and, in the absence of this enzyme, by its cognate isoenzyme MAOB. MAOA and A/B knockout (KO) mice display high 5-HT levels, particularly during early developmental stages. Here we show that both mutant lines exhibit numerous behavioural hallmarks of ASDs, such as social and communication impairments, perseverative and stereotypical responses, behavioural inflexibility, as well as subtle tactile and motor deficits. Furthermore, both MAOA and A/B KO mice displayed neuropathological alterations reminiscent of typical ASD features, including reduced thickness of the corpus callosum, increased dendritic arborization of pyramidal neurons in the prefrontal cortex and disrupted microarchitecture of the cerebellum. The severity of repetitive responses and neuropathological aberrances was generally greater in MAOA/B KO animals. These findings suggest that the neurochemical imbalances induced by MAOA deficiency (either by itself or in conjunction with lack of MAOB) may result in an array of abnormalities similar to those observed in ASDs. Thus, MAOA and A/B KO mice may afford valuable models to help elucidate the neurobiological bases of these disorders and related neurodevelopmental problems.

PMID: 22850464 [PubMed - indexed for MEDLINE]

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