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Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice.

December 22, 2015 - 7:31am
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Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice.

PLoS One. 2014;9(10):e109527

Authors: Park MJ, Aja S, Li Q, Degano AL, Penati J, Zhuo J, Roe CR, Ronnett GV

Abstract
Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2). Symptoms range in severity and include psychomotor disabilities, seizures, ataxia, and intellectual disability. Symptom onset is between 6-18 months of age, a critical period of brain development that is highly energy-dependent. Notably, patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal levels of the adipokines leptin and adiponectin, suggesting overall metabolic imbalance. We hypothesized that one contributor to RTT symptoms is energy deficiency due to defective nutrient substrate utilization by the TCA cycle. This energy deficit would lead to a metabolic imbalance, but would be treatable by providing anaplerotic substrates to the TCA cycle to enhance energy production. We show that dietary therapy with triheptanoin significantly increased longevity and improved motor function and social interaction in male mice hemizygous for Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved indicators of impaired substrate utilization, decreased adiposity, increased glucose tolerance and insulin sensitivity, decreased serum leptin and insulin, and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics of liver and skeletal muscle revealed increases in levels of TCA cycle intermediates with triheptanoin diet, as well as normalizations of glucose and fatty acid biochemical pathways consistent with the improved metabolic phenotype in Mecp2 knockout mice on triheptanoin. These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in RTT.

PMID: 25299635 [PubMed - indexed for MEDLINE]

Prevalence of Creatine Deficiency Syndromes in Children With Nonsyndromic Autism.

December 20, 2015 - 7:26am

Prevalence of Creatine Deficiency Syndromes in Children With Nonsyndromic Autism.

Pediatrics. 2015 Dec 18;

Authors: Schulze A, Bauman M, Tsai AC, Reynolds A, Roberts W, Anagnostou E, Cameron J, Nozzolillo AA, Chen S, Kyriakopoulou L, Scherer SW, Loh A

Abstract
BACKGROUND AND OBJECTIVE: Creatine deficiency may play a role in the neurobiology of autism and may represent a treatable cause of autism. The goal of the study was to ascertain the prevalence of creatine deficiency syndromes (CDSs) in children with autism spectrum disorder (ASD).
METHODS: In a prospective multicenter study, 443 children were investigated after a confirmed diagnosis of ASD. Random spot urine screening for creatine metabolites (creatine, guanidinoacetate, creatinine, and arginine) with liquid chromatography-tandem mass spectrometry and second-tier testing with high-performance liquid chromatography methodology was followed by recall testing in 24-hour urines and confirmatory testing by Sanger-based DNA sequencing of GAMT, GATM, and SLC6A8 genes. Additional diagnostic tests included plasma creatine metabolites and in vivo brain proton magnetic resonance spectroscopy. The creatine metabolites in spot urine in the autism group were compared with 128 healthy controls controlled for age.
RESULTS: In 443 subjects with ASD investigated for CDS, we had 0 events (event: 0, 95% confidence interval 0-0.0068), therefore with 95% confidence the prevalence of CDS is <7 in 1000 children with ASD. The autism and control groups did not vary in terms of creatine metabolites (P > .0125) in urine.
CONCLUSION: Our study revealed a very low prevalence of CDS in children with nonsyndromic ASD and no obvious association between creatine metabolites and autism. Unlike our study population, we expect more frequent CDS among children with severe developmental delay, speech impairment, seizures, and movement disorders in addition to impairments in social communication, restricted interests, and repetitive behaviors.

PMID: 26684475 [PubMed - as supplied by publisher]

Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders.

December 19, 2015 - 7:25am
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Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders.

Curr Mol Med. 2015;15(2):146-67

Authors: Gao R, Penzes P

Abstract
Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism. Thus, understanding the molecular underpinnings of E/I imbalance may provide essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.

PMID: 25732149 [PubMed - indexed for MEDLINE]

Analysis of CHRNA7 rare variants in autism spectrum disorder susceptibility.

December 19, 2015 - 7:25am
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Analysis of CHRNA7 rare variants in autism spectrum disorder susceptibility.

Am J Med Genet A. 2015 Apr;167A(4):715-23

Authors: Bacchelli E, Battaglia A, Cameli C, Lomartire S, Tancredi R, Thomson S, Sutcliffe JS, Maestrini E

Abstract
Chromosome 15q13.3 recurrent microdeletions are causally associated with a wide range of phenotypes, including autism spectrum disorder (ASD), seizures, intellectual disability, and other psychiatric conditions. Whether the reciprocal microduplication is pathogenic is less certain. CHRNA7, encoding for the alpha7 subunit of the neuronal nicotinic acetylcholine receptor, is considered the likely culprit gene in mediating neurological phenotypes in 15q13.3 deletion cases. To assess if CHRNA7 rare variants confer risk to ASD, we performed copy number variant analysis and Sanger sequencing of the CHRNA7 coding sequence in a sample of 135 ASD cases. Sequence variation in this gene remains largely unexplored, given the existence of a fusion gene, CHRFAM7A, which includes a nearly identical partial duplication of CHRNA7. Hence, attempts to sequence coding exons must distinguish between CHRNA7 and CHRFAM7A, making next-generation sequencing approaches unreliable for this purpose. A CHRNA7 microduplication was detected in a patient with autism and moderate cognitive impairment; while no rare damaging variants were identified in the coding region, we detected rare variants in the promoter region, previously described to functionally reduce transcription. This study represents the first sequence variant analysis of CHRNA7 in a sample of idiopathic autism.

PMID: 25655306 [PubMed - indexed for MEDLINE]

An inherited small microdeletion at 15q13.3 in a patient with early-onset obsessive-compulsive disorder.

December 19, 2015 - 7:25am
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An inherited small microdeletion at 15q13.3 in a patient with early-onset obsessive-compulsive disorder.

PLoS One. 2014;9(10):e110198

Authors: Cappi C, Hounie AG, Mariani DB, Diniz JB, Silva AR, Reis VN, Busso AF, Silva AG, Fidalgo F, Rogatto SR, Miguel EC, Krepischi AC, Brentani H

Abstract
Copy number variations (CNVs) have been previously associated with several different neurodevelopmental psychiatric disorders, such as autism, schizophrenia, and attention deficit hyperactivity disorder (ADHD). The present study consisted of a pilot genome-wide screen for CNVs in a cohort of 16 patients with early-onset obsessive-compulsive disorder (OCD) and 12 mentally healthy individuals, using array-based comparative genomic hybridization (aCGH) on 44K arrays. A small rare paternal inherited microdeletion (∼64 kb) was identified in chromosome 15q13.3 of one male patient with very early onset OCD. The father did not have OCD. The deletion encompassed part of the FMN1 gene, which is involved with the glutamatergic system. This finding supports the hypothesis of a complex network of several genes expressed in the brain contributing for the genetic risk of OCD, and also supports the glutamatergic involvement in OCD, which has been previously reported in the literature.

PMID: 25303678 [PubMed - indexed for MEDLINE]

De novo TBR1 mutations in sporadic autism disrupt protein functions.

December 19, 2015 - 7:25am
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De novo TBR1 mutations in sporadic autism disrupt protein functions.

Nat Commun. 2014;5:4954

Authors: Deriziotis P, O'Roak BJ, Graham SA, Estruch SB, Dimitropoulou D, Bernier RA, Gerdts J, Shendure J, Eichler EE, Fisher SE

Abstract
Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.

PMID: 25232744 [PubMed - indexed for MEDLINE]

Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel.

December 19, 2015 - 7:25am
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Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel.

PLoS One. 2014;9(4):e93409

Authors: Brett M, McPherson J, Zang ZJ, Lai A, Tan ES, Ng I, Ong LC, Cham B, Tan P, Rozen S, Tan EC

Abstract
Developmental delay and/or intellectual disability (DD/ID) affects 1-3% of all children. At least half of these are thought to have a genetic etiology. Recent studies have shown that massively parallel sequencing (MPS) using a targeted gene panel is particularly suited for diagnostic testing for genetically heterogeneous conditions. We report on our experiences with using massively parallel sequencing of a targeted gene panel of 355 genes for investigating the genetic etiology of eight patients with a wide range of phenotypes including DD/ID, congenital anomalies and/or autism spectrum disorder. Targeted sequence enrichment was performed using the Agilent SureSelect Target Enrichment Kit and sequenced on the Illumina HiSeq2000 using paired-end reads. For all eight patients, 81-84% of the targeted regions achieved read depths of at least 20×, with average read depths overlapping targets ranging from 322× to 798×. Causative variants were successfully identified in two of the eight patients: a nonsense mutation in the ATRX gene and a canonical splice site mutation in the L1CAM gene. In a third patient, a canonical splice site variant in the USP9X gene could likely explain all or some of her clinical phenotypes. These results confirm the value of targeted MPS for investigating DD/ID in children for diagnostic purposes. However, targeted gene MPS was less likely to provide a genetic diagnosis for children whose phenotype includes autism.

PMID: 24690944 [PubMed - indexed for MEDLINE]

DUF1220 copy number is associated with schizophrenia risk and severity: implications for understanding autism and schizophrenia as related diseases.

December 17, 2015 - 7:21am

DUF1220 copy number is associated with schizophrenia risk and severity: implications for understanding autism and schizophrenia as related diseases.

Transl Psychiatry. 2015;5:e697

Authors: Searles Quick VB, Davis JM, Olincy A, Sikela JM

Abstract
The copy number of DUF1220, a protein domain implicated in human brain evolution, has been linearly associated with autism severity. Given the possibility that autism and schizophrenia are related disorders, the present study examined DUF1220 copy number variation in schizophrenia severity. There are notable similarities between autism symptoms and schizophrenia negative symptoms, and divergence between autism symptoms and schizophrenia positive symptoms. We therefore also examined DUF1220 copy number in schizophrenia subgroups defined by negative and positive symptom features, versus autistic individuals and controls. In the schizophrenic population (N=609), decreased DUF1220 copy number was linearly associated with increasing positive symptom severity (CON1 P=0.013, HLS1 P=0.0227), an association greatest in adult-onset schizophrenia (CON1 P=0.00155, HLS1 P=0.00361). In schizophrenic males, DUF1220 CON1 subtype copy number increase was associated with increased negative symptom severity (P=0.0327), a finding similar to that seen in autistic populations. Subgroup analyses demonstrated that schizophrenic individuals with predominantly positive symptoms exhibited reduced CON1 copy number compared with both controls (P=0.0237) and schizophrenic individuals with predominantly negative symptoms (P=0.0068). These findings support the view that (1) autism and schizophrenia exhibit both opposing and partially overlapping phenotypes and may represent a disease continuum, (2) variation in DUF1220 copy number contributes to schizophrenia disease risk and to the severity of both disorders, and (3) schizophrenia and autism may be, in part, a harmful by-product of the rapid and extreme evolutionary increase in DUF1220 copy number in the human species.

PMID: 26670282 [PubMed - as supplied by publisher]

Structure and function of neonatal social communication in a genetic mouse model of autism.

December 17, 2015 - 7:21am

Structure and function of neonatal social communication in a genetic mouse model of autism.

Mol Psychiatry. 2015 Dec 15;

Authors: Takahashi T, Okabe S, Broin PÓ, Nishi A, Ye K, Beckert MV, Izumi T, Machida A, Kang G, Abe S, Pena JL, Golden A, Kikusui T, Hiroi N

Abstract
A critical step toward understanding autism spectrum disorder (ASD) is to identify both genetic and environmental risk factors. A number of rare copy number variants (CNVs) have emerged as robust genetic risk factors for ASD, but not all CNV carriers exhibit ASD and the severity of ASD symptoms varies among CNV carriers. Although evidence exists that various environmental factors modulate symptomatic severity, the precise mechanisms by which these factors determine the ultimate severity of ASD are still poorly understood. Here, using a mouse heterozygous for Tbx1 (a gene encoded in 22q11.2 CNV), we demonstrate that a genetically triggered neonatal phenotype in vocalization generates a negative environmental loop in pup-mother social communication. Wild-type pups used individually diverse sequences of simple and complicated call types, but heterozygous pups used individually invariable call sequences with less complicated call types. When played back, representative wild-type call sequences elicited maternal approach, but heterozygous call sequences were ineffective. When the representative wild-type call sequences were randomized, they were ineffective in eliciting vigorous maternal approach behavior. These data demonstrate that an ASD risk gene alters the neonatal call sequence of its carriers and this pup phenotype in turn diminishes maternal care through atypical social communication. Thus, an ASD risk gene induces, through atypical neonatal call sequences, less than optimal maternal care as a negative neonatal environmental factor.Molecular Psychiatry advance online publication, 15 December 2015; doi:10.1038/mp.2015.190.

PMID: 26666205 [PubMed - as supplied by publisher]

Dysregulation and restoration of translational homeostasis in fragile X syndrome.

December 17, 2015 - 7:21am
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Dysregulation and restoration of translational homeostasis in fragile X syndrome.

Nat Rev Neurosci. 2015 Oct;16(10):595-605

Authors: Richter JD, Bassell GJ, Klann E

Abstract
Fragile X syndrome (FXS), the most-frequently inherited form of intellectual disability and the most-prevalent single-gene cause of autism, results from a lack of fragile X mental retardation protein (FMRP), an RNA-binding protein that acts, in most cases, to repress translation. Multiple pharmacological and genetic manipulations that target receptors, scaffolding proteins, kinases and translational control proteins can rescue neuronal morphology, synaptic function and behavioural phenotypes in FXS model mice, presumably by reducing excessive neuronal translation to normal levels. Such rescue strategies might also be explored in the future to identify the mRNAs that are critical for FXS pathophysiology.

PMID: 26350240 [PubMed - indexed for MEDLINE]

Sex-Specific Placental Responses in Fetal Development.

December 17, 2015 - 7:21am
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Sex-Specific Placental Responses in Fetal Development.

Endocrinology. 2015 Oct;156(10):3422-34

Authors: Rosenfeld CS

Abstract
The placenta is an ephemeral but critical organ for the survival of all eutherian mammals and marsupials. It is the primary messenger system between the mother and fetus, where communicational signals, nutrients, waste, gases, and extrinsic factors are exchanged. Although the placenta may buffer the fetus from various environmental insults, placental dysfunction might also contribute to detrimental developmental origins of adult health and disease effects. The placenta of one sex over the other might possess greater ability to respond and buffer against environmental insults. Given the potential role of the placenta in effecting the lifetime health of the offspring, it is not surprising that there has been a resurging interest in this organ, including the Human Placental Project launched by the National Institutes of Child Health and Human Development. In this review, we will compare embryological development of the laboratory mouse and human chorioallantoic placentae. Next, evidence that various species, including humans, exhibit normal sex-dependent structural and functional placental differences will be examined followed by how in utero environmental changes (nutritional state, stress, and exposure to environmental chemicals) might interact with fetal sex to affect this organ. Recent data also suggest that paternal state impacts placental function in a sex-dependent manner. The research to date linking placental maladaptive responses and later developmental origins of adult health and disease effects will be explored. Finally, we will focus on how sex chromosomes and epimutations may contribute to sex-dependent differences in placental function, the unanswered questions, and future directions that warrant further consideration.

PMID: 26241064 [PubMed - indexed for MEDLINE]

Psychopathological manifestations of joint hypermobility and joint hypermobility syndrome/ Ehlers-Danlos syndrome, hypermobility type: The link between connective tissue and psychological distress revised.

December 17, 2015 - 7:21am
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Psychopathological manifestations of joint hypermobility and joint hypermobility syndrome/ Ehlers-Danlos syndrome, hypermobility type: The link between connective tissue and psychological distress revised.

Am J Med Genet C Semin Med Genet. 2015 Mar;169C(1):97-106

Authors: Sinibaldi L, Ursini G, Castori M

Abstract
Psychological distress is a known feature of generalized joint hypermobility (gJHM), as well as of its most common syndromic presentation, namely Ehlers-Danlos syndrome, hypermobility type (a.k.a. joint hypermobility syndrome - JHS/EDS-HT), and significantly contributes to the quality of life of affected individuals. Most published articles dealt with the link between gJHM (or JHS/EDS-HT) and anxiety-related conditions, and a novel generation of studies is emerging aimed at investigating the psychopathologic background of such an association. In this paper, literature review was carried out with a semi-systematic approach spanning the entire spectrum of psychopathological findings in gJHM and JHS/EDS-HT. Interestingly, in addition to the confirmation of a tight link between anxiety and gJHM, preliminary connections with depression, attention deficit (and hyperactivity) disorder, autism spectrum disorders, and obsessive-compulsive personality disorder were also found. Few papers investigated the relationship with schizophrenia with contrasting results. The mind-body connections hypothesized on the basis of available data were discussed with focus on somatotype, presumed psychopathology, and involvement of the extracellular matrix in the central nervous system. The hypothesis of positive Beighton score and alteration of interoceptive/proprioceptive/body awareness as possible endophenotypes in families with symptomatic gJHM or JHS/EDS-HT is also suggested. Concluding remarks addressed the implications of the psychopathological features of gJHM and JHS/EDS-HT in clinical practice.

PMID: 25821094 [PubMed - indexed for MEDLINE]

Identification of rare causal variants in sequence-based studies: methods and applications to VPS13B, a gene involved in Cohen syndrome and autism.

December 17, 2015 - 7:21am
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Identification of rare causal variants in sequence-based studies: methods and applications to VPS13B, a gene involved in Cohen syndrome and autism.

PLoS Genet. 2014 Dec;10(12):e1004729

Authors: Ionita-Laza I, Capanu M, De Rubeis S, McCallum K, Buxbaum JD

Abstract
Pinpointing the small number of causal variants among the abundant naturally occurring genetic variation is a difficult challenge, but a crucial one for understanding precise molecular mechanisms of disease and follow-up functional studies. We propose and investigate two complementary statistical approaches for identification of rare causal variants in sequencing studies: a backward elimination procedure based on groupwise association tests, and a hierarchical approach that can integrate sequencing data with diverse functional and evolutionary conservation annotations for individual variants. Using simulations, we show that incorporation of multiple bioinformatic predictors of deleteriousness, such as PolyPhen-2, SIFT and GERP++ scores, can improve the power to discover truly causal variants. As proof of principle, we apply the proposed methods to VPS13B, a gene mutated in the rare neurodevelopmental disorder called Cohen syndrome, and recently reported with recessive variants in autism. We identify a small set of promising candidates for causal variants, including two loss-of-function variants and a rare, homozygous probably-damaging variant that could contribute to autism risk.

PMID: 25502226 [PubMed - indexed for MEDLINE]

No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia.

December 17, 2015 - 7:21am
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No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia.

Eur J Hum Genet. 2015 Apr;23(4):555-7

Authors: Ruderfer DM, Lim ET, Genovese G, Moran JL, Hultman CM, Sullivan PF, McCarroll SA, Holmans P, Sklar P, Purcell SM

Abstract
Recessive inheritance of gene disrupting alleles, either through homozygosity at a specific site or compound heterozygosity, have been demonstrated to underlie many Mendelian diseases and some complex psychiatric disorders. On the basis of exome sequencing data, an increased burden of complete knockout (homozygous or compound heterozygous) variants has been identified in autism. In addition, using single-nucleotide polymorphism microarray data, an increased rate of homozygosity by descent, or autozygosity, has been linked to the risk of schizophrenia (SCZ). Here, in a large Swedish case-control SCZ sample (11 244 individuals, 5079 of whom have exome sequence data available), we survey the contribution of both autozygosity and complete knockouts to disease risk. We do not find evidence for association with SCZ, either genome wide or at specific loci. However, we note the possible impact of sample size and population genetic factors on the power to detect and quantify any burden that may exist.

PMID: 25370044 [PubMed - indexed for MEDLINE]

De novo EEF1A2 mutations in patients with characteristic facial features, intellectual disability, autistic behaviors and epilepsy.

December 17, 2015 - 7:21am
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De novo EEF1A2 mutations in patients with characteristic facial features, intellectual disability, autistic behaviors and epilepsy.

Clin Genet. 2015 Apr;87(4):356-61

Authors: Nakajima J, Okamoto N, Tohyama J, Kato M, Arai H, Funahashi O, Tsurusaki Y, Nakashima M, Kawashima H, Saitsu H, Matsumoto N, Miyake N

Abstract
Eukaryotic elongation factor 1, alpha-2 (eEF1A2) protein is involved in protein synthesis, suppression of apoptosis, and regulation of actin function and cytoskeletal structure. EEF1A2 gene is highly expressed in the central nervous system and Eef1a2 knockout mice show the neuronal degeneration. Until now, only one missense mutation (c.208G > A, p.Gly70Ser) in EEF1A2 has been reported in two independent patients with neurological disease. In this report, we described two patients with de novo mutations (c.754G > C, p.Asp252His and c.364G > A, p.Glu122Lys) in EEF1A2 found by whole-exome sequencing. Common clinical features are shared by all four individuals: severe intellectual disability, autistic behavior, absent speech, neonatal hypotonia, epilepsy and progressive microcephaly. Furthermore, the two patients share the similar characteristic facial features including a depressed nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth. These data strongly indicate that a new recognizable disorder is caused by EEF1A2 mutations.

PMID: 24697219 [PubMed - indexed for MEDLINE]

[Alteration of Social Behaviors in Male Mice of CBA/Lac Strain under Agonistic Interactions].

December 15, 2015 - 1:17pm
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[Alteration of Social Behaviors in Male Mice of CBA/Lac Strain under Agonistic Interactions].

Zh Vyssh Nerv Deiat Im I P Pavlova. 2015 Jul-Aug;65(4):486-97

Authors: Kovalenko IL, Kudryavtseva NN

Abstract
Ability of people to communicate with each other is a necessary component of social behavior and normal development of individuals living in community. A pronounced impairment in communication may be the result of autism which is characterized by impaired socialization, low communication and restricted and/or repetitive behaviors. It is hypothesized that genes or rare mutations play a key role in the development of autism. However a multifold increase of the cases with autistic spectrum symptoms over the last years cannot be attributed exclusively to genetic mutations or heredity. Environmental contribution to the development of autistic symptoms has to be considered. The paper aimed to analyze the social behaviors of CBA/Lac mice with repeated experience of aggression or social defeats in daily agonistic interactions with accent on searches of associations with autistic symptoms in comparison with previously studied C57BL/6J animals. It has been shown that male mice of both strains with alternative social behaviors demonstrated the changes in social behaviors; however the expression of some form of behaviors was different. The data obtained to assert that long-term hostile social environment lead to development of disturbances in social behaviors, accompanying by autistic-like symptoms.

PMID: 26601507 [PubMed - indexed for MEDLINE]

Autism Spectrum Disorder - A Complex Genetic Disorder.

December 15, 2015 - 1:17pm
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Autism Spectrum Disorder - A Complex Genetic Disorder.

Folia Med (Plovdiv). 2015 Jan-Mar;57(1):19-28

Authors: Ivanov HY, Stoyanova VK, Popov NT, Vachev TI

Abstract
Autism spectrum disorder is an entity that reflects a scientific consensus that several previously separated disorders are actually a single spectrum disorder with different levels of symptom severity in two core domains - deficits in social communication and interaction, and restricted repetitive behaviors. Autism spectrum disorder is diagnosed in all racial, ethnic and socioeconomic groups and because of its increased prevalence, reported worldwide through the last years, made it one of the most discussed child psychiatric disorders. In term of aetiology as several other complex diseases, Autism spectrum disorder is considered to have a strong genetic component.

PMID: 26431091 [PubMed - indexed for MEDLINE]

Neurotrophin-3 Enhances the Synaptic Organizing Function of TrkC-Protein Tyrosine Phosphatase σ in Rat Hippocampal Neurons.

December 15, 2015 - 1:17pm
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Neurotrophin-3 Enhances the Synaptic Organizing Function of TrkC-Protein Tyrosine Phosphatase σ in Rat Hippocampal Neurons.

J Neurosci. 2015 Sep 9;35(36):12425-31

Authors: Ammendrup-Johnsen I, Naito Y, Craig AM, Takahashi H

Abstract
Neurotrophin-3 (NT-3) and its high-affinity receptor TrkC play crucial trophic roles in neuronal differentiation, axon outgrowth, and synapse development and plasticity in the nervous system. We demonstrated previously that postsynaptic TrkC functions as a glutamatergic synapse-inducing (synaptogenic) cell adhesion molecule trans-interacting with presynaptic protein tyrosine phosphatase σ (PTPσ). Given that NT-3 and PTPσ bind distinct domains of the TrkC extracellular region, here we tested the hypothesis that NT-3 modulates TrkC/PTPσ binding and synaptogenic activity. NT-3 enhanced PTPσ binding to cell surface-expressed TrkC and facilitated the presynapse-inducing activity of TrkC in rat hippocampal neurons. Imaging of recycling presynaptic vesicles combined with TrkC knockdown and rescue approaches demonstrated that NT-3 rapidly potentiates presynaptic function via binding endogenous postsynaptic TrkC in a tyrosine kinase-independent manner. Thus, NT-3 positively modulates the TrkC-PTPσ complex for glutamatergic presynaptic assembly and function independently from TrkC kinase activation. Our findings provide new insight into synaptic roles of neurotrophin signaling and mechanisms controlling synaptic organizing complexes. Significance statement: Although many synaptogenic adhesion complexes have been identified in recent years, little is known about modulatory mechanisms. Here, we demonstrate a novel role of neurotrophin-3 in synaptic assembly and function as a positive modulator of the TrkC-protein tyrosine phosphatase σ complex. This study provides new insight into the involvement of neurotrophin signaling in synapse development and plasticity, presenting a molecular mechanism that may underlie previous observations of short- and long-term enhancement of presynaptic function by neurotrophin. Given the links of synaptogenic adhesion molecules to autism and schizophrenia, this study might also contribute to a better understanding of the pathogenesis of these disorders and provide a new direction for ameliorating imbalances in synaptic signaling networks.

PMID: 26354911 [PubMed - indexed for MEDLINE]

Modeling psychiatric disorders for developing effective treatments.

December 15, 2015 - 1:17pm
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Modeling psychiatric disorders for developing effective treatments.

Nat Med. 2015 Sep;21(9):979-88

Authors: Kaiser T, Feng G

Abstract
Recent advances in identifying risk-associated genes have provided unprecedented opportunities for developing animal models for psychiatric disease research with the goal of attaining translational utility to ultimately develop novel treatments. However, at this early stage, successful translation has yet to be achieved. Here we review recent advances in modeling psychiatric disease, discuss the utility and limitations of animal models, and emphasize the importance of shifting from behavioral analysis to identifying neurophysiological abnormalities, which are likely to be more conserved across species and thus may increase translatability. Looking forward, we envision that preclinical research will align with clinical research to build a common framework of comparable neurobiological abnormalities and to help form subgroups of patients on the basis of similar pathophysiology. Experimental neuroscience can then use animal models to discover mechanisms underlying distinct abnormalities and develop strategies for effective treatments.

PMID: 26340119 [PubMed - indexed for MEDLINE]

Karyopherin α 3 and karyopherin α 4 proteins mediate the nuclear import of methyl-CpG binding protein 2.

December 15, 2015 - 1:17pm
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Karyopherin α 3 and karyopherin α 4 proteins mediate the nuclear import of methyl-CpG binding protein 2.

J Biol Chem. 2015 Sep 11;290(37):22485-93

Authors: Baker SA, Lombardi LM, Zoghbi HY

Abstract
Methyl-CpG binding protein 2 (MeCP2) is a nuclear protein with important roles in regulating chromatin structure and gene expression, and mutations in MECP2 cause Rett syndrome (RTT). Within the MeCP2 protein sequence, the nuclear localization signal (NLS) is reported to reside between amino acids 255-271, and certain RTT-causing mutations overlap with the MeCP2 NLS, suggesting that they may alter nuclear localization. One such mutation, R270X, is predicted to interfere with the localization of MeCP2, but recent in vivo studies have demonstrated that this mutant remains entirely nuclear. To clarify the mechanism of MeCP2 nuclear import, we isolated proteins that interact with the NLS and identified karyopherin α 3 (KPNA3 or Kap-α3) and karyopherin α 4 (KPNA4 or Kap-α4) as key binding partners of MeCP2. MeCP2-R270X did not interact with KPNA4, consistent with a requirement for an intact NLS in this interaction. However, this mutant retains binding to KPNA3, accounting for the normal localization of MeCP2-R270X to the nucleus. These data provide a mechanism for MeCP2 nuclear import and have implications for the design of therapeutics aimed at modulating the function of MeCP2 in RTT patients.

PMID: 26245896 [PubMed - indexed for MEDLINE]

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