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CDKL5 variant in a boy with infantile epileptic encephalopathy: case report.

December 15, 2015 - 1:17pm
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CDKL5 variant in a boy with infantile epileptic encephalopathy: case report.

Brain Dev. 2015 Apr;37(4):446-8

Authors: Wong VC, Kwong AK

Abstract
UNLABELLED: A Chinese boy presented at 18 months with intractable epilepsy, developmental delay and autistic features. He had multiple seizure types, including absence, myoclonic seizures, limb spasm and tonic seizures. His seizures were finally controlled at 3 years of age with clonazepam and a short course of chloral hydrate incidentally given for his insomnia. Subsequently, he had improvement in his communication skills.
RESULT: A novel hemizygous missense variant (c.1649G>A; p.R550Q) in exon 12 of CDKL5 gene was detected for him, his asymptomatic mother and elder sister. His phenotype is less severe than other male cases.
CONCLUSION: We recommend screening CDKL5 for boys with pharmarco-resistant epilepsy and a trial of benzodiazepines for Infantile Epileptic Encephalopathy (IEE).

PMID: 25085838 [PubMed - indexed for MEDLINE]

Studies of human sex ratios at birth may lead to the understanding of several forms of pathology.

December 15, 2015 - 1:17pm
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Studies of human sex ratios at birth may lead to the understanding of several forms of pathology.

Hum Biol. 2013 Oct;85(5):769-88

Authors: James WH

Abstract
This article deals with the problem of the causes of the variation of sex ratio (proportion male) at birth. This problem is common to a number of areas in biology and medicine, for example, obstetrics, neurology/psychiatry, parasitology, virology, oncology, and teratology. It is established that there are signifi cantly biased, but unexplained, sex ratios in each of these fields. Yet workers in them (with the possible exception of virology) have regarded the problem as a minor loose end, irrelevant to the field's major problems. However, as far as I know, no one has previously noted that unexplained biased sex ratios occur, and thus pose (perhaps similar) problems, in all these fields. Here it is suggested that similar sorts of solutions apply in each. Further research is proposed for testing each solution. If the argument here is substantially correct across this range of topics, it may lead to an improved understanding not only of sex ratio but also of some of the pathologies in these specialties.

PMID: 25078960 [PubMed - indexed for MEDLINE]

Cell adhesion proteins and the pathogenesis of autism spectrum disorders.

December 15, 2015 - 1:17pm
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Cell adhesion proteins and the pathogenesis of autism spectrum disorders.

J Neurophysiol. 2015 Mar 1;113(5):1283-6

Authors: Stewart LT

Abstract
Current theories on the pathogenesis of autism spectrum disorders (ASD) maintain that the associated cognitive and behavioral symptoms are caused by aberrant synaptic transmission affecting specific brain circuits. Transgenic mouse models have implicated the involvement of cell adhesion proteins in synaptic dysfunction and ASD pathogenesis. Recently, Aoto et al. (Cell 154: 75-88, 2013) has shown that alternatively spliced neurexin proteins affect the efficacy of AMPA receptor-mediated excitatory currents in both cultured neuronal networks and acute hippocampal slices constituting a potential ASD-related electrophysiological phenotype.

PMID: 24990562 [PubMed - indexed for MEDLINE]

Broader autism phenotype in mothers predicts social responsiveness in young children with autism spectrum disorders.

December 15, 2015 - 1:17pm
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Broader autism phenotype in mothers predicts social responsiveness in young children with autism spectrum disorders.

Psychiatry Clin Neurosci. 2015 Mar;69(3):136-44

Authors: Hasegawa C, Kikuchi M, Yoshimura Y, Hiraishi H, Munesue T, Nakatani H, Higashida H, Asada M, Oi M, Minabe Y

Abstract
AIMS: The aim of this study was to identify phenotypes in mothers and fathers that are specifically associated with disturbances in reciprocal social interactions and communication in their young children with autism spectrum disorder (ASD) in a Japanese sample.
METHODS: Autistic traits in parents were evaluated using the Autism-spectrum Quotient (AQ), the Empathy Quotient (EQ) and the Systemizing Quotient (SQ) in 88 parents (44 mothers and corresponding fathers) of children with ASD and in 60 parents (30 mothers and corresponding fathers) of typically developing (TD) children. For the measurement of autistic traits in children, we employed the Social Responsiveness Scale (SRS).
RESULTS: In two of the five AQ subscales (social skills and communication), the parents of ASD children scored significantly higher than did the parents of TD children, regardless of whether the parent was a mother or a father. In addition, in mothers of ASD children, there were significant positive correlations between two of the five AQ subscales (attention-switching and communication) and the SRS T-score in their children.
CONCLUSIONS: This is the first study to demonstrate that the social skills and communication subscales in the AQ are more sensitive as autism traits in a Japanese sample and to demonstrate that some autistic traits in mothers are specifically associated with disturbances in the social ability of their young children with ASD, as measured by the SRS score. Further study is necessary to determine whether these results were caused by genetic or environmental factors.

PMID: 24902617 [PubMed - indexed for MEDLINE]

Resequencing and association analysis of OXTR with autism spectrum disorder in a Japanese population.

December 15, 2015 - 1:17pm
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Resequencing and association analysis of OXTR with autism spectrum disorder in a Japanese population.

Psychiatry Clin Neurosci. 2015 Mar;69(3):131-5

Authors: Egawa J, Watanabe Y, Shibuya M, Endo T, Sugimoto A, Igeta H, Nunokawa A, Inoue E, Someya T

Abstract
AIMS: The oxytocin receptor (OXTR) is implicated in the pathophysiology of autism spectrum disorder (ASD). A recent study found a rare non-synonymous OXTR gene variation, rs35062132 (R376G), associated with ASD in a Japanese population. In order to investigate the association between rare non-synonymous OXTR variations and ASD, we resequenced OXTR and performed association analysis with ASD in a Japanese population.
METHODS: We resequenced the OXTR coding region in 213 ASD patients. Rare non-synonymous OXTR variations detected by resequencing were genotyped in 213 patients and 667 controls.
RESULTS: We detected three rare non-synonymous variations: rs35062132 (R376G/C), rs151257822 (G334D), and g.8809426G>T (R150S). However, there was no significant association between these rare non-synonymous variations and ASD.
CONCLUSIONS: Our present study does not support the contribution of rare non-synonymous OXTR variations to ASD susceptibility in the Japanese population.

PMID: 24836510 [PubMed - indexed for MEDLINE]

Cdk5 phosphorylation of ErbB4 is required for tangential migration of cortical interneurons.

December 15, 2015 - 1:17pm
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Cdk5 phosphorylation of ErbB4 is required for tangential migration of cortical interneurons.

Cereb Cortex. 2015 Apr;25(4):991-1003

Authors: Rakić S, Kanatani S, Hunt D, Faux C, Cariboni A, Chiara F, Khan S, Wansbury O, Howard B, Nakajima K, Nikolić M, Parnavelas JG

Abstract
Interneuron dysfunction in humans is often associated with neurological and psychiatric disorders, such as epilepsy, schizophrenia, and autism. Some of these disorders are believed to emerge during brain formation, at the time of interneuron specification, migration, and synapse formation. Here, using a mouse model and a host of histological and molecular biological techniques, we report that the signaling molecule cyclin-dependent kinase 5 (Cdk5), and its activator p35, control the tangential migration of interneurons toward and within the cerebral cortex by modulating the critical neurodevelopmental signaling pathway, ErbB4/phosphatidylinositol 3-kinase, that has been repeatedly linked to schizophrenia. This finding identifies Cdk5 as a crucial signaling factor in cortical interneuron development in mammals.

PMID: 24142862 [PubMed - indexed for MEDLINE]

Absence of deficits in social behaviors and ultrasonic vocalizations in later generations of mice lacking neuroligin4.

December 15, 2015 - 1:17pm
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Absence of deficits in social behaviors and ultrasonic vocalizations in later generations of mice lacking neuroligin4.

Genes Brain Behav. 2012 Nov;11(8):928-41

Authors: Ey E, Yang M, Katz AM, Woldeyohannes L, Silverman JL, Leblond CS, Faure P, Torquet N, Le Sourd AM, Bourgeron T, Crawley JN

Abstract
Mutations in NLGN4X have been identified in individuals with autism spectrum disorders and other neurodevelopmental disorders. A previous study reported that adult male mice lacking neuroligin4 (Nlgn4) displayed social approach deficits in the three-chambered test, altered aggressive behaviors and reduced ultrasonic vocalizations. To replicate and extend these findings, independent comprehensive analyses of autism-relevant behavioral phenotypes were conducted in later generations of the same line of Nlgn4 mutant mice at the National Institute of Mental Health in Bethesda, MD, USA and at the Institut Pasteur in Paris, France. Adult social approach was normal in all three genotypes of Nlgn4 mice tested at both sites. Reciprocal social interactions in juveniles were similarly normal across genotypes. No genotype differences were detected in ultrasonic vocalizations in pups separated from the nest or in adults during reciprocal social interactions. Anxiety-like behaviors, self-grooming, rotarod and open field exploration did not differ across genotypes, and measures of developmental milestones and general health were normal. Our findings indicate an absence of autism-relevant behavioral phenotypes in subsequent generations of Nlgn4 mice tested at two locations. Testing environment and methods differed from the original study in some aspects, although the presence of normal sociability was seen in all genotypes when methods taken from Jamain et al. (2008) were used. The divergent results obtained from this study indicate that phenotypes may not be replicable across breeding generations, and highlight the significant roles of environmental, generational and/or procedural factors on behavioral phenotypes.

PMID: 22989184 [PubMed - indexed for MEDLINE]

Family history interview of a broad phenotype in specific language impairment and matched controls.

December 15, 2015 - 1:17pm
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Family history interview of a broad phenotype in specific language impairment and matched controls.

Genes Brain Behav. 2012 Nov;11(8):921-7

Authors: Kalnak N, Peyrard-Janvid M, Sahlén B, Forssberg H

Abstract
The aim was to study a broader phenotype of language-related diagnoses and problems in three generations of relatives of children with specific language impairment (SLI). Our study is based on a family history interview of the parents of 59 children with SLI and of 100 matched control children, exploring the prevalence of problems related to language, reading, attention, school achievement and social communication as well as diagnoses such as attention-deficit hyperactivity disorder (ADHD), autism, Asperger syndrome, dyslexia, mental retardation, cleft palate and stuttering. The results show a spectrum of language-related problems in families of SLI children. In all three generations of SLI relatives, we found significantly higher prevalence rates of language, literacy and social communication problems. The risk of one or both parents having language-related diagnoses or problems was approximately six times higher for the children with SLI (85%) than for the control children (13%) (odds ratio = 37.2). We did not find a significantly higher prevalence of the diagnoses ADHD, autism or Asperger syndrome in the relatives of the children with SLI. However, significantly more parents of the children with SLI had problems with attention/hyperactivity when compared with the parents of controls. Our findings suggest common underlying mechanisms for problems with language, literacy and social communication, and possibly also for attention/hyperactivity symptoms.

PMID: 22928858 [PubMed - indexed for MEDLINE]

Altered Hippocampal Neurogenesis and Amygdalar Neuronal Activity in Adult Mice with Repeated Experience of Aggression.

December 10, 2015 - 6:32am

Altered Hippocampal Neurogenesis and Amygdalar Neuronal Activity in Adult Mice with Repeated Experience of Aggression.

Front Neurosci. 2015;9:443

Authors: Smagin DA, Park JH, Michurina TV, Peunova N, Glass Z, Sayed K, Bondar NP, Kovalenko IN, Kudryavtseva NN, Enikolopov G

Abstract
Repeated experience of winning in a social conflict setting elevates levels of aggression and may lead to violent behavioral patterns. Here, we use a paradigm of repeated aggression and fighting deprivation to examine changes in behavior, neurogenesis, and neuronal activity in mice with positive fighting experience. We show that for males, repeated positive fighting experience induces persistent demonstration of aggression and stereotypic behaviors in daily agonistic interactions, enhances aggressive motivation, and elevates levels of anxiety. When winning males are deprived of opportunities to engage in further fights, they demonstrate increased levels of aggressiveness. Positive fighting experience results in increased levels of progenitor cell proliferation and production of young neurons in the hippocampus. This increase is not diminished after a fighting deprivation period. Furthermore, repeated winning experience decreases the number of activated (c-fos-positive) cells in the basolateral amygdala and increases the number of activated cells in the hippocampus; a subsequent no-fight period restores the number of c-fos-positive cells. Our results indicate that extended positive fighting experience in a social conflict heightens aggression, increases proliferation of neuronal progenitors and production of young neurons in the hippocampus, and decreases neuronal activity in the amygdala; these changes can be modified by depriving the winners of the opportunity for further fights.

PMID: 26648838 [PubMed - as supplied by publisher]

Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.

December 10, 2015 - 6:32am
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Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.

Hum Mol Genet. 2015 Dec 8;

Authors: Sollis E, Graham SA, Vino A, Froehlich H, Vreeburg M, Dimitropoulou D, Gilissen C, Pfundt R, Rappold GA, Brunner HG, Deriziotis P, Fisher SE

Abstract
De novo disruptions of the neural transcription factor FOXP1 are a recently discovered, rare cause of sporadic intellectual disability. We report three new cases of FOXP1-related disorder identified through clinical whole-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment.

PMID: 26647308 [PubMed - as supplied by publisher]

Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target?

December 10, 2015 - 6:32am
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Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target?

Mol Genet Metab. 2015 Nov 17;

Authors: Horvath GA, Demos M, Shyr C, Matthews A, Zhang L, Race S, Stockler-Ipsiroglu S, Van Allen MI, Mancarci O, Toker L, Pavlidis P, Ross CJ, Wasserman WW, Trump N, Heales S, Pope S, Helen Cross J, van Karnebeek CD

Abstract
We describe neurotransmitter abnormalities in two patients with drug-resistant epilepsy resulting from deleterious de novo mutations in sodium channel genes. Whole exome sequencing identified a de novo SCN2A splice-site mutation (c.2379+1G>A, p.Glu717Gly.fs*30) resulting in deletion of exon 14, in a 10-year old male with early onset global developmental delay, intermittent ataxia, autism, hypotonia, epileptic encephalopathy and cerebral/cerebellar atrophy. In the cerebrospinal fluid both homovanillic acid and 5-hydroxyindoleacetic acid were significantly decreased; extensive biochemical and genetic investigations ruled out primary neurotransmitter deficiencies and other known inborn errors of metabolism. In an 8-year old female with an early onset intractable epileptic encephalopathy, developmental regression, and progressive cerebellar atrophy, a previously unreported de novo missense mutation was identified in SCN8A (c.5615G>A; p.Arg1872Gln), affecting a highly conserved residue located in the C-terminal of the Nav1.6 protein. Aside from decreased homovanillic acid and 5-hydroxyindoleacetic acid, 5-methyltetrahydrofolate was also found to be low. We hypothesize that these channelopathies cause abnormal synaptic mono-amine metabolite secretion/uptake via impaired vesicular release and imbalance in electrochemical ion gradients, which in turn aggravate the seizures. Treatment with oral 5-hydroxytryptophan, l-Dopa/Carbidopa, and a dopa agonist resulted in mild improvement of seizure control in the male case, most likely via dopamine and serotonin receptor activated signal transduction and modulation of glutamatergic, GABA-ergic and glycinergic neurotransmission. Neurotransmitter analysis in other sodium channelopathy patients will help validate our findings, potentially yielding novel treatment opportunities.

PMID: 26647175 [PubMed - as supplied by publisher]

RNA binding proteins, neural development and the addictions.

December 9, 2015 - 6:25am

RNA binding proteins, neural development and the addictions.

Genes Brain Behav. 2015 Dec 8;

Authors: Bryant CD, Yazdani N

Abstract
Transcriptional and post-transcriptional regulation of gene expression defines the neurobiological mechanisms that bridge genetic and environmental risk factors with neurobehavioral dysfunction underlying the addictions. More than 1000 genes in the eukaryotic genome code for multifunctional RNA binding proteins (RBPs) that can regulate all levels of RNA biogenesis. More than 50% of these RBPs are expressed in the brain where they regulate alternative splicing, transport, localization, stability, and translation of RNAs during development and adulthood. RBP dysfunction can exert global effects on their targetomes that underlie neurodegenerative disorders such as Alzheimer's and Parkinson's disease as well as neurodevelopmental disorders, including autism and schizophrenia. Here, we consider the evidence that RBPs influence key molecular targets, neurodevelopment, synaptic plasticity, and neurobehavioral dysfunction underlying the addictions. Increasingly well-powered genome-wide association studies in humans and mammalian model organisms combined with ever more precise transcriptomic and proteomic approaches will continue to uncover novel and possibly selective roles for RBPs in the addictions. Key challenges include identifying the biological functions of the dynamic RBP targetomes from specific cell types throughout subcellular space (e.g., the nuclear spliceome versus the synaptic translatome) and time and manipulating RBP programs through post-transcriptional modifications to prevent or reverse aberrant neurodevelopment and plasticity underlying the addictions.

PMID: 26643147 [PubMed - as supplied by publisher]

Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.

December 8, 2015 - 6:21am
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Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.

Neuron. 2015 Dec 2;88(5):910-7

Authors: D'Gama AM, Pochareddy S, Li M, Jamuar SS, Reiff RE, Lam AT, Sestan N, Walsh CA

Abstract
Single nucleotide variants (SNVs), particularly loss-of-function mutations, are significant contributors to autism spectrum disorder (ASD) risk. Here we report the first systematic deep sequencing study of 55 postmortem ASD brains for SNVs in 78 known ASD candidate genes. Remarkably, even without parental samples, we find more ASD brains with mutations that are protein-altering (26/55 cases versus 12/50 controls, p = 0.015), deleterious (16/55 versus 5/50, p = 0.016), or loss-of-function (6/55 versus 0/50, p = 0.028) compared to controls, with recurrent deleterious mutations in ARID1B, SCN1A, SCN2A, and SETD2, suggesting these mutations contribute to ASD risk. In several cases, the identified mutations and medical records suggest syndromic ASD diagnoses. Two ASD and one Fragile X premutation case showed deleterious somatic mutations, providing evidence that somatic mutations occur in ASD cases, and supporting a model in which a combination of germline and/or somatic mutations may contribute to ASD risk on a case-by-case basis.

PMID: 26637798 [PubMed - in process]

Hippocampal Transcriptomic and Proteomic Alterations in the BTBR Mouse Model of Autism Spectrum Disorder.

December 5, 2015 - 8:02am

Hippocampal Transcriptomic and Proteomic Alterations in the BTBR Mouse Model of Autism Spectrum Disorder.

Front Physiol. 2015;6:324

Authors: Daimon CM, Jasien JM, Wood WH, Zhang Y, Becker KG, Silverman JL, Crawley JN, Martin B, Maudsley S

Abstract
Autism spectrum disorders (ASD) are complex heterogeneous neurodevelopmental disorders of an unclear etiology, and no cure currently exists. Prior studies have demonstrated that the black and tan, brachyury (BTBR) T+ Itpr3tf/J mouse strain displays a behavioral phenotype with ASD-like features. BTBR T+ Itpr3tf/J mice (referred to simply as BTBR) display deficits in social functioning, lack of communication ability, and engagement in stereotyped behavior. Despite extensive behavioral phenotypic characterization, little is known about the genes and proteins responsible for the presentation of the ASD-like phenotype in the BTBR mouse model. In this study, we employed bioinformatics techniques to gain a wide-scale understanding of the transcriptomic and proteomic changes associated with the ASD-like phenotype in BTBR mice. We found a number of genes and proteins to be significantly altered in BTBR mice compared to C57BL/6J (B6) control mice controls such as BDNF, Shank3, and ERK1, which are highly relevant to prior investigations of ASD. Furthermore, we identified distinct functional pathways altered in BTBR mice compared to B6 controls that have been previously shown to be altered in both mouse models of ASD, some human clinical populations, and have been suggested as a possible etiological mechanism of ASD, including "axon guidance" and "regulation of actin cytoskeleton." In addition, our wide-scale bioinformatics approach also discovered several previously unidentified genes and proteins associated with the ASD phenotype in BTBR mice, such as Caskin1, suggesting that bioinformatics could be an avenue by which novel therapeutic targets for ASD are uncovered. As a result, we believe that informed use of synergistic bioinformatics applications represents an invaluable tool for elucidating the etiology of complex disorders like ASD.

PMID: 26635614 [PubMed - as supplied by publisher]

JAKMIP1, a Novel Regulator of Neuronal Translation, Modulates Synaptic Function and Autistic-like Behaviors in Mouse.

December 3, 2015 - 7:59am
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JAKMIP1, a Novel Regulator of Neuronal Translation, Modulates Synaptic Function and Autistic-like Behaviors in Mouse.

Neuron. 2015 Nov 25;

Authors: Berg JM, Lee C, Chen L, Galvan L, Cepeda C, Chen JY, Peñagarikano O, Stein JL, Li A, Oguro-Ando A, Miller JA, Vashisht AA, Starks ME, Kite EP, Tam E, Gdalyahu A, Al-Sharif NB, Burkett ZD, White SA, Fears SC, Levine MS, Wohlschlegel JA, Geschwind DH

Abstract
Autism spectrum disorder (ASD) is a heritable, common neurodevelopmental disorder with diverse genetic causes. Several studies have implicated protein synthesis as one among several of its potential convergent mechanisms. We originally identified Janus kinase and microtubule-interacting protein 1 (JAKMIP1) as differentially expressed in patients with distinct syndromic forms of ASD, fragile X syndrome, and 15q duplication syndrome. Here, we provide multiple lines of evidence that JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes fragile X mental retardation protein, DEAD box helicase 5, and the poly(A) binding protein cytoplasmic 1. JAKMIP1 loss dysregulates neuronal translation during synaptic development, affecting glutamatergic NMDAR signaling, and results in social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors in the mouse. These findings define an important and novel role for JAKMIP1 in neural development and further highlight pathways regulating mRNA translation during synaptogenesis in the genesis of neurodevelopmental disorders.

PMID: 26627310 [PubMed - as supplied by publisher]

Mutation of genes controlling mRNA metabolism and protein synthesis predisposes to neurodevelopmental disorders.

November 29, 2015 - 7:31am

Mutation of genes controlling mRNA metabolism and protein synthesis predisposes to neurodevelopmental disorders.

Biochem Soc Trans. 2015 Dec 1;43(6):1259-65

Authors: Sartor F, Anderson J, McCaig C, Miedzybrodzka Z, Müller B

Abstract
Brain development is a tightly controlled process that depends upon differentiation and function of neurons to allow for the formation of functional neural networks. Mutation of genes encoding structural proteins is well recognized as causal for neurodevelopmental disorders (NDDs). Recent studies have shown that aberrant gene expression can also lead to disorders of neural development. Here we summarize recent evidence implicating in the aetiology of NDDs mutation of factors acting at the level of mRNA splicing, mRNA nuclear export, translation and mRNA degradation. This highlights the importance of these fundamental processes for human health and affords new strategies and targets for therapeutic intervention.

PMID: 26614670 [PubMed - in process]

Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes.

November 28, 2015 - 7:14am

Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes.

EMBO Mol Med. 2015 Nov 26;

Authors: Stepniak B, Kästner A, Poggi G, Mitjans M, Begemann M, Hartmann A, Van der Auwera S, Sananbenesi F, Krueger-Burg D, Matuszko G, Brosi C, Homuth G, Völzke H, Benseler F, Bagni C, Fischer U, Dityatev A, Grabe HJ, Rujescu D, Fischer A, Ehrenreich H

Abstract
Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high- versus low-risk constellation regarding the accumulation model. Thereby, the brain-expressed miR-181 species emerged as potential "umbrella regulator", with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes.

PMID: 26612855 [PubMed - as supplied by publisher]

Histone Modifier Genes Alter Conotruncal Heart Phenotypes in 22q11.2 Deletion Syndrome.

November 27, 2015 - 7:12am

Histone Modifier Genes Alter Conotruncal Heart Phenotypes in 22q11.2 Deletion Syndrome.

Am J Hum Genet. 2015 Nov 18;

Authors: Guo T, Chung JH, Wang T, McDonald-McGinn DM, Kates WR, Hawuła W, Coleman K, Zackai E, Emanuel BS, Morrow BE

Abstract
We performed whole exome sequence (WES) to identify genetic modifiers on 184 individuals with 22q11.2 deletion syndrome (22q11DS), of whom 89 case subjects had severe congenital heart disease (CHD) and 95 control subjects had normal hearts. Three genes including JMJD1C (jumonji domain containing 1C), RREB1 (Ras responsive element binding protein 1), and SEC24C (SEC24 family member C) had rare (MAF < 0.001) predicted deleterious single-nucleotide variations (rdSNVs) in seven case subjects and no control subjects (p = 0.005; Fisher exact and permutation tests). Because JMJD1C and RREB1 are involved in chromatin modification, we investigated other histone modification genes. Eighteen case subjects (20%) had rdSNVs in four genes (JMJD1C, RREB1, MINA, KDM7A) all involved in demethylation of histones (H3K9, H3K27). Overall, rdSNVs were enriched in histone modifier genes that activate transcription (Fisher exact p = 0.0004, permutations, p = 0.0003, OR = 5.16); however, rdSNVs in control subjects were not enriched. This implicates histone modification genes as influencing risk for CHD in presence of the deletion.

PMID: 26608785 [PubMed - as supplied by publisher]

Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides.

November 26, 2015 - 7:09am

Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides.

Nature. 2015 Nov 25;

Authors: Sztainberg Y, Chen HM, Swann JW, Hao S, Tang B, Wu Z, Tang J, Wan YW, Liu Z, Rigo F, Zoghbi HY

Abstract
Copy number variations have been frequently associated with developmental delay, intellectual disability and autism spectrum disorders. MECP2 duplication syndrome is one of the most common genomic rearrangements in males and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death. The broad range of deficits caused by methyl-CpG-binding protein 2 (MeCP2) overexpression poses a daunting challenge to traditional biochemical-pathway-based therapeutic approaches. Accordingly, we sought strategies that directly target MeCP2 and are amenable to translation into clinical therapy. The first question that we addressed was whether the neurological dysfunction is reversible after symptoms set in. Reversal of phenotypes in adult symptomatic mice has been demonstrated in some models of monogenic loss-of-function neurological disorders, including loss of MeCP2 in Rett syndrome, indicating that, at least in some cases, the neuroanatomy may remain sufficiently intact so that correction of the molecular dysfunction underlying these disorders can restore healthy physiology. Given the absence of neurodegeneration in MECP2 duplication syndrome, we propose that restoration of normal MeCP2 levels in MECP2 duplication adult mice would rescue their phenotype. By generating and characterizing a conditional Mecp2-overexpressing mouse model, here we show that correction of MeCP2 levels largely reverses the behavioural, molecular and electrophysiological deficits. We also reduced MeCP2 using an antisense oligonucleotide strategy, which has greater translational potential. Antisense oligonucleotides are small, modified nucleic acids that can selectively hybridize with messenger RNA transcribed from a target gene and silence it, and have been successfully used to correct deficits in different mouse models. We find that antisense oligonucleotide treatment induces a broad phenotypic rescue in adult symptomatic transgenic MECP2 duplication mice (MECP2-TG), and corrected MECP2 levels in lymphoblastoid cells from MECP2 duplication patients in a dose-dependent manner.

PMID: 26605526 [PubMed - as supplied by publisher]

Urine Pyrimidine Metabolite Determination by HPLC Tandem Mass Spectrometry.

November 26, 2015 - 7:09am

Urine Pyrimidine Metabolite Determination by HPLC Tandem Mass Spectrometry.

Methods Mol Biol. 2016;1378:237-42

Authors: Sun Q

Abstract
Pyrimidine diseases result from deficiencies in pyrimidine de novo synthesis, degradation, and salvage pathways. Enzymatic deficiencies in pyrimidine catabolism lead to mitochondrial neurogastrointestinal encephalopathy (MNGIE), pyrimidinuria, dihydropyrimidinuria, ureidopropionic aciduria, and other disorders. While MNGIE presents with gastrointestinal dysmotility, cachexia, and leukoencephalopathy, pyrimidinuria and dihydropyrimidinuria may show symptoms of epilepsy, autism, mental retardation, and dysmorphic features. The application of HPLC-MS/MS facilitates rapid screening of pyrimidine metabolites. Here we describe an LCMS method for determination of uracil, thymine, thymidine, dihydrouracil, and dihydrothymine that are diagnostic biomarkers of MNGIE, pyrimidinuria, and dihydropyrimidinuria.

PMID: 26602135 [PubMed - in process]

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