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Role of parental occupation in autism spectrum disorder diagnosis and severity.

July 16, 2014 - 8:37am
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Role of parental occupation in autism spectrum disorder diagnosis and severity.

Res Autism Spectr Disord. 2014 Sep 1;8(9):997-1007

Authors: Dickerson AS, Pearson DA, Loveland KA, Rahbar MH, Filipek PA

PMID: 25024741 [PubMed - as supplied by publisher]

Autism susceptibility genes and the transcriptional landscape of the human brain.

July 16, 2014 - 8:37am
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Autism susceptibility genes and the transcriptional landscape of the human brain.

Int Rev Neurobiol. 2013;113:303-18

Authors: Miyauchi S, Voineagu I

Abstract
Autism is the most severe end of a spectrum of neurodevelopmental conditions, autism spectrum disorders (ASD). ASD are genetically heterogeneous, and hundreds of genes have been implicated in the etiology of the disease. Here, we discuss the contribution of brain transcriptome studies in advancing our understanding of the genetic mechanisms of ASD and review recent work characterizing the spatial and temporal variation of the human brain transcriptome, with a focus on the relevance of these data to autism susceptibility genes.

PMID: 24290390 [PubMed - indexed for MEDLINE]

Orchestration of neurodevelopmental programs by RBFOX1: implications for autism spectrum disorder.

July 16, 2014 - 8:37am
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Orchestration of neurodevelopmental programs by RBFOX1: implications for autism spectrum disorder.

Int Rev Neurobiol. 2013;113:251-67

Authors: Bill BR, Lowe JK, Dybuncio CT, Fogel BL

Abstract
Neurodevelopmental and neuropsychiatric disorders result from complex interactions between critical genetic factors and as-yet-unknown environmental components. To gain clinical insight, it is critical to develop a comprehensive understanding of these genetic components. RBFOX1, an RNA splicing factor, regulates expression of large genetic networks during early neuronal development, and haploinsufficiency causes severe neurodevelopmental phenotypes including autism spectrum disorder (ASD), intellectual disability, and epilepsy. Genomic testing in individuals and large patient cohorts has identified phenotypically similar cases possessing copy number variations in RBFOX1, implicating the gene as an important cause of neurodevelopmental disease. However, a significant proportion of the observed structural variation is inherited from phenotypically normal individuals, raising questions regarding overall pathogenicity of variation at the RBFOX1 locus. In this chapter, we discuss the molecular, cellular, and clinical evidence supporting the role of RBFOX1 in neurodevelopment and present a comprehensive model for the contribution of structural variation in RBFOX1 to ASD.

PMID: 24290388 [PubMed - indexed for MEDLINE]

Transcriptional dysregulation of neocortical circuit assembly in ASD.

July 16, 2014 - 8:37am
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Transcriptional dysregulation of neocortical circuit assembly in ASD.

Int Rev Neurobiol. 2013;113:167-205

Authors: Kwan KY

Abstract
Autism spectrum disorders (ASDs) impair social cognition and communication, key higher-order functions centered in the human neocortex. The assembly of neocortical circuitry is a precisely regulated developmental process susceptible to genetic alterations that can ultimately affect cognitive abilities. Because ASD is an early onset neurodevelopmental disorder that disrupts functions executed by the neocortex, miswiring of neocortical circuits has been hypothesized to be an underlying mechanism of ASD. This possibility is supported by emerging genetic findings and data from imaging studies. Recent research on neocortical development has identified transcription factors as key determinants of neocortical circuit assembly, mediating diverse processes including neuronal specification, migration, and wiring. Many of these TFs (TBR1, SOX5, FEZF2, and SATB2) have been implicated in ASD. Here, I will discuss the functional roles of these transcriptional programs in neocortical circuit development and their neurobiological implications for the emerging etiology of ASD.

PMID: 24290386 [PubMed - indexed for MEDLINE]

MET receptor tyrosine kinase as an autism genetic risk factor.

July 16, 2014 - 8:37am
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MET receptor tyrosine kinase as an autism genetic risk factor.

Int Rev Neurobiol. 2013;113:135-65

Authors: Peng Y, Huentelman M, Smith C, Qiu S

Abstract
In this chapter, we will briefly discuss recent literature on the role of MET receptor tyrosine kinase (RTK) in brain development and how perturbation of MET signaling may alter normal neurodevelopmental outcomes. Recent human genetic studies have established MET as a risk factor for autism, and the molecular and cellular underpinnings of this genetic risk are only beginning to emerge from obscurity. Unlike many autism risk genes that encode synaptic proteins, the spatial and temporal expression pattern of MET RTK indicates this signaling system is ideally situated to regulate neuronal growth, functional maturation, and establishment of functional brain circuits, particularly in those brain structures involved in higher levels of cognition, social skills, and executive functions.

PMID: 24290385 [PubMed - indexed for MEDLINE]

Connecting signaling pathways underlying communication to ASD vulnerability.

July 16, 2014 - 8:37am
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Connecting signaling pathways underlying communication to ASD vulnerability.

Int Rev Neurobiol. 2013;113:97-133

Authors: Lepp S, Anderson A, Konopka G

Abstract
Language is a human-specific trait that likely facilitated the rapid increase in higher cognitive function in our species. A consequence of the selective pressures that have permitted language and cognition to flourish in humans is the unique vulnerability of humans to developing cognitive disorders such as autism. Therefore, progress in understanding the genetic and molecular mechanisms of language evolution should provide insight into such disorders. Here, we discuss the few genes that have been identified in both autism-related pathways and language. We also detail the use of animal models to uncover the function of these genes at a mechanistic and circuit level. Finally, we present the use of comparative genomics to identify novel genes and gene networks involved in autism. Together, all of these approaches will allow for a broader and deeper view of the molecular brain mechanisms involved in the evolution of language and the gene disruptions associated with autism.

PMID: 24290384 [PubMed - indexed for MEDLINE]

Identifying essential cell types and circuits in autism spectrum disorders.

July 16, 2014 - 8:37am
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Identifying essential cell types and circuits in autism spectrum disorders.

Int Rev Neurobiol. 2013;113:61-96

Authors: Maloney SE, Rieger MA, Dougherty JD

Abstract
Autism spectrum disorder (ASD) is highly genetic in its etiology, with potentially hundreds of genes contributing to risk. Despite this heterogeneity, these disparate genetic lesions may result in the disruption of a limited number of key cell types or circuits-information which could be leveraged for the design of therapeutic interventions. While hypotheses for cellular disruptions can be identified by postmortem anatomical analysis and expression studies of ASD risk genes, testing these hypotheses requires the use of animal models. In this review, we explore the existing evidence supporting the contribution of different cell types to ASD, specifically focusing on rodent studies disrupting serotonergic, GABAergic, cerebellar, and striatal cell types, with particular attention to studies of the sufficiency of specific cellular disruptions to generate ASD-related behavioral abnormalities. This evidence suggests multiple cellular routes can create features of the disorder, though it is currently unclear if these cell types converge on a final common circuit. We hope that in the future, systematic studies of cellular sufficiency and genetic interaction will help to classify patients into groups by type of cellular disruptions which suggest tractable therapeutic targets.

PMID: 24290383 [PubMed - indexed for MEDLINE]

Contribution of long noncoding RNAs to autism spectrum disorder risk.

July 16, 2014 - 8:37am
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Contribution of long noncoding RNAs to autism spectrum disorder risk.

Int Rev Neurobiol. 2013;113:35-59

Authors: Wilkinson B, Campbell DB

Abstract
Accumulating evidence indicates that long noncoding RNAs (lncRNAs) contribute to autism spectrum disorder (ASD) risk. Although a few lncRNAs have long been recognized to have important functions, the vast majority of this class of molecules remains uncharacterized. Because lncRNAs are more abundant in human brain than protein-coding RNAs, it is likely that they contribute to brain disorders, including ASD. We review here the known functions of lncRNAs and the potential contributions of lncRNAs to ASD.

PMID: 24290382 [PubMed - indexed for MEDLINE]

Autism spectrum disorder and the cerebellum.

July 16, 2014 - 8:37am
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Autism spectrum disorder and the cerebellum.

Int Rev Neurobiol. 2013;113:1-34

Authors: Becker EB, Stoodley CJ

Abstract
The cerebellum has been long known for its importance in motor learning and coordination. Recently, anatomical, clinical, and neuroimaging studies strongly suggest that the cerebellum supports cognitive functions, including language and executive functions, as well as affective regulation. Furthermore, the cerebellum has emerged as one of the key brain regions affected in autism. Here, we discuss our current understanding of the role of the cerebellum in autism, including evidence from genetic, molecular, clinical, behavioral, and neuroimaging studies. Cerebellar findings in autism suggest developmental differences at multiple levels of neural structure and function, indicating that the cerebellum is an important player in the complex neural underpinnings of autism spectrum disorder, with behavioral implications beyond the motor domain.

PMID: 24290381 [PubMed - indexed for MEDLINE]

[Autism and epigenetics. A model of explanation for the understanding of the genesis in autism spectrum disorders].

July 16, 2014 - 8:37am
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[Autism and epigenetics. A model of explanation for the understanding of the genesis in autism spectrum disorders].

Medicina (B Aires). 2013;73 Suppl 1:20-9

Authors: Arberas C, Ruggieri V

Abstract
Autism spectrum disorders are characterized by impairment of social integration and language development and restricted interests. Autism spectrum disorders manifest during childhood and may have a varying clinical expression over the years related to different therapeutic approaches, behavior-modifying drugs, and environmental factors, among others. So far, the genetic alterations identified are not sufficient to explain the genesis of all these processes, as many of the mutations found are also present in unaffected individuals. Findings on the underlying biological and pathophysiological mechanisms of entities strongly associated with autism spectrum disorders, such as Rett, fragile X, Angelman, and fetal alcohol syndromes, point to the role of epigenetic changes in disorders of neurodevelopment. Epigenetic phenomena are normal biological processes necessary for cell and thus human life, especially related to embryonic development. Different phenomena that affect epigenetic processes (changes that change operation or expression of a gene, without modifying the DNA structure) have also been shown to be important in the genesis of neurodevelopmental disorders. Alterations in the epigenetic mechanism may be reversible, which may explain the variation in the autism phenotype over time. Here we analyze the normal epigenetic mechanisms, autism spectrum disorders, their association with specific entities associated with altered epigenetic mechanisms, and possible therapeutic approaches targeting these alterations.

PMID: 24072048 [PubMed - indexed for MEDLINE]

Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis.

July 16, 2014 - 8:37am
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Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis.

J Med Genet. 2013 Nov;50(11):733-9

Authors: Edvardson S, Ashikov A, Jalas C, Sturiale L, Shaag A, Fedick A, Treff NR, Garozzo D, Gerardy-Schahn R, Elpeleg O

Abstract
BACKGROUND: The heritability of autism spectrum disorder is currently estimated at 55%. Identification of the molecular basis of patients with syndromic autism extends our understanding of the pathogenesis of autism in general. The objective of this study was to find the gene mutated in eight patients from a large kindred, who suffered from autism spectrum disorder, arthrogryposis and epilepsy.
METHODS AND RESULTS: By linkage analysis and exome sequencing, we identified deleterious mutations in SLC35A3 in these patients. SLC35A3 encodes the major Golgi uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter. In Golgi vesicles isolated from patient fibroblasts the transport of the respective nucleotide sugar was significantly reduced causing a massive decrease in the content of cell surface expressed highly branched N-glycans and a concomitant sharp increase of lower branched glycoforms.
CONCLUSIONS: Spontaneous mutation in SLC35A3 has been discovered in cattle worldwide, recapitulating the human phenotype with arthrogryposis and additional skeletal defects known as Complex Vertebral Malformation syndrome. The skeletal anomalies in the mutant cattle and in our patients, and perhaps even the neurological symptoms are likely the consequence of the lack of high-branched N-glycans and the concomitant abundance of lower-branched glycoforms at the cell surface. This pattern has previously been associated with growth arrest and induction of differentiation. With this study, we add SLC35A3 to the gene list of autism spectrum disorders, and underscore the crucial importance of UDP-GlcNAc in the regulation of the N-glycan branching pathway in the Golgi apparatus.

PMID: 24031089 [PubMed - indexed for MEDLINE]

ADHD, autism spectrum disorder, temperament, and character: phenotypical associations and etiology in a Swedish childhood twin study.

July 16, 2014 - 8:37am
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ADHD, autism spectrum disorder, temperament, and character: phenotypical associations and etiology in a Swedish childhood twin study.

Compr Psychiatry. 2013 Nov;54(8):1140-7

Authors: Kerekes N, Brändström S, Lundström S, Råstam M, Nilsson T, Anckarsäter H

Abstract
OBJECTIVE: To explore the links between neurodevelopmental disorders - attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) - and personality in a population-based, genetically sensitive study of children.
METHOD: A population-based sample of 1886 twins aged 9 and 12, enriched for childhood mental health problems, was recruited from the Child and Adolescent Twin Study in Sweden (CATSS). Parents were interviewed over the telephone using the Autism-Tics, AD/HD and other Comorbidities (A-TAC) inventory, and in a second step they rated their children according to the Junior Temperament and Character Inventory (JTCI).
RESULTS: ADHD was strongly correlated with novelty seeking, while ASD was correlated positively with harm avoidance and negatively with reward dependence. The strongest associations between personality traits and neurodevelopmental disorders were negative correlations between the character dimensions of self-directedness and cooperativeness and ADHD and ASD alike. Cross-twin cross-trait correlations between ADHD, ASD, and personality dimensions in monozygotic twins were more than double those in dizygotic twins, indicating a strong genetic effect behind the phenotypic covariation between neurodevelopmental disorders and personality.
CONCLUSIONS: Neurodevelopmental disorders are linked specifically to particular temperament profiles and generally to hampered development of the self-governing strategies referred to as "character." Poor self-agency and cooperation may be core functional outcomes in the separation of children with handicapping conditions from those with traits only reminiscent of neurodevelopmental disorders. The associations between neurodevelopmental disorders and personality are at least partly due to genetic effects influencing both conditions. As a consequence, personality must be broadly considered in neuropsychiatry, just as neuropsychiatric disorders and their genetic, neurodevelopmental, and cognitive susceptibilities have to be in personality research and clinical treatment.

PMID: 23790516 [PubMed - indexed for MEDLINE]

Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly.

July 16, 2014 - 8:37am
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Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly.

J Med Genet. 2013 Nov;50(11):740-4

Authors: Capo-Chichi JM, Tcherkezian J, Hamdan FF, Décarie JC, Dobrzeniecka S, Patry L, Nadon MA, Mucha BE, Major P, Shevell M, Bencheikh BO, Joober R, Samuels ME, Rouleau GA, Roux PP, Michaud JL

Abstract
BACKGROUND: Mutations in TSC1 or TSC2 cause the tuberous sclerosis complex (TSC), a disorder characterised by the development of hamartomas or benign tumours in various organs as well as the variable presence of epilepsy, intellectual disability (ID) and autism. TSC1, TSC2 and the recently described protein TBC1D7 form a complex that inhibits mTORC1 signalling and limits cell growth. Although it has been proposed that mutations in TBC1D7 might also cause TSC, loss of its function has not yet been documented in humans.
METHODS AND RESULTS: We used homozygosity mapping and exome sequencing to study a consanguineous family with ID and megalencephaly but without any specific features of TSC. We identified only one rare coding variant, c.538delT:p.Y180fsX1 in TBC1D7, in the regions of homozygosity shared by the affected siblings. We show that this mutation abolishes TBC1D7 expression and is associated with increased mTORC1 signalling in cells of the affected individuals.
CONCLUSIONS: Our study suggests that disruption of TBC1D7 causes ID but without the other typical features found in TSC. Although megalencephaly is not commonly observed in TSC, it has been associated with mTORC1 activation. Our observation thus reinforces the relationship between this pathway and the development of megalencephaly.

PMID: 23687350 [PubMed - indexed for MEDLINE]

Insights into GABAAergic System Deficits in Fragile X Syndrome Lead to Clinical Trials.

July 13, 2014 - 7:11am

Insights into GABAAergic System Deficits in Fragile X Syndrome Lead to Clinical Trials.

Neuropharmacology. 2014 Jul 9;

Authors: Braat S, Kooy RF

Abstract
An increasing number of studies implicate the GABAAergic system in the pathophysiology of the fragile X syndrome, a frequent cause of intellectual disability and autism. Animal models have proven invaluable in unravelling the molecular mechanisms underlying the disorder. Multiple defects in this inhibitory system have been identified in Fmr1 knockout mice, including altered expression of various components, aberrant GABAA receptor-mediated signalling, altered GABA concentrations and anatomical defects in GABAergic neurons. Aberrations compatible with those described in the mouse model were detected in dfmr1 deficient Drosophila melanogaster, a validated fly model for the fragile X syndrome. Treatment with drugs that ameliorate the GABAAergic deficiency in both animal models have demonstrated that the GABAA receptor is a promising target for the treatment of fragile X patients. Based on these preclinical studies, clinical trials in patients have been initiated.

PMID: 25016041 [PubMed - as supplied by publisher]

Neural Signatures of Autism Spectrum Disorders: Insights into Brain Network Dynamics.

July 12, 2014 - 6:22am

Neural Signatures of Autism Spectrum Disorders: Insights into Brain Network Dynamics.

Neuropsychopharmacology. 2014 Jul 11;

Authors: Hernandez LM, Rudie JD, Green SA, Bookheimer S, Dapretto M

Abstract
Neuroimaging investigations of Autism Spectrum Disorders (ASDs) have advanced our understanding of atypical brain function and structure, and have recently converged on a model of altered network-level connectivity. Traditional task-based functional magnetic resonance imaging (MRI) and volume-based structural MRI studies have identified widespread atypicalities in brain regions involved in social behavior and other core ASD-related behavioral deficits. More recent advances in MR-neuroimaging methods allow for quantification of brain connectivity using diffusion tensor imaging, functional connectivity, and graph theoretic methods. These newer techniques have moved the field toward a systems-level understanding of ASD etiology, integrating functional and structural measures across distal brain regions. Neuroimaging findings in ASD as a whole have been mixed and at times contradictory, likely due to the vast genetic and phenotypic heterogeneity characteristic of the disorder. Future longitudinal studies of brain development will be crucial to yield insights into mechanisms of disease etiology in ASD subpopulations. Advances in neuroimaging methods and large-scale collaborations will also allow for an integrated approach linking neuroimaging, genetics, and phenotypic data.Neuropsychopharmacology Reviews accepted article preview online, 11 July 2014; doi:10.1038/npp.2014.172.

PMID: 25011468 [PubMed - as supplied by publisher]

Age-Associated Sperm DNA Methylation Alterations: Possible Implications in Offspring Disease Susceptibility.

July 11, 2014 - 3:05pm
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Age-Associated Sperm DNA Methylation Alterations: Possible Implications in Offspring Disease Susceptibility.

PLoS Genet. 2014 Jul;10(7):e1004458

Authors: Jenkins TG, Aston KI, Pflueger C, Cairns BR, Carrell DT

Abstract
Recent evidence demonstrates a role for paternal aging on offspring disease susceptibility. It is well established that various neuropsychiatric disorders (schizophrenia, autism, etc.), trinucleotide expansion associated diseases (myotonic dystrophy, Huntington's, etc.) and even some forms of cancer have increased incidence in the offspring of older fathers. Despite strong epidemiological evidence that these alterations are more common in offspring sired by older fathers, in most cases the mechanisms that drive these processes are unclear. However, it is commonly believed that epigenetics, and specifically DNA methylation alterations, likely play a role. In this study we have investigated the impact of aging on DNA methylation in mature human sperm. Using a methylation array approach we evaluated changes to sperm DNA methylation patterns in 17 fertile donors by comparing the sperm methylome of 2 samples collected from each individual 9-19 years apart. With this design we have identified 139 regions that are significantly and consistently hypomethylated with age and 8 regions that are significantly hypermethylated with age. A representative subset of these alterations have been confirmed in an independent cohort. A total of 117 genes are associated with these regions of methylation alterations (promoter or gene body). Intriguingly, a portion of the age-related changes in sperm DNA methylation are located at genes previously associated with schizophrenia and bipolar disorder. While our data does not establish a causative relationship, it does raise the possibility that the age-associated methylation of the candidate genes that we observe in sperm might contribute to the increased incidence of neuropsychiatric and other disorders in the offspring of older males. However, further study is required to determine whether, and to what extent, a causative relationship exists.

PMID: 25010591 [PubMed - as supplied by publisher]

Dissociable Genetic Contributions to Error Processing: A Multimodal Neuroimaging Study.

July 11, 2014 - 3:05pm
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Dissociable Genetic Contributions to Error Processing: A Multimodal Neuroimaging Study.

PLoS One. 2014;9(7):e101784

Authors: Agam Y, Vangel M, Roffman JL, Gallagher PJ, Chaponis J, Haddad S, Goff DC, Greenberg JL, Wilhelm S, Smoller JW, Manoach DS

Abstract
BACKGROUND: Neuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation.
METHODS: We measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response.
RESULTS: We replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant.
CONCLUSIONS: DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation.

PMID: 25010186 [PubMed - as supplied by publisher]

PACAP and PAC1 receptor in brain development and behavior.

July 11, 2014 - 3:05pm
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PACAP and PAC1 receptor in brain development and behavior.

Neuropeptides. 2013 Dec;47(6):421-30

Authors: Shen S, Gehlert DR, Collier DA

Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) act through three class B G-protein coupled receptors, PAC1, VPAC1 and VPAC2, initiating multiple signaling pathways. In addition to natural peptides ligands, a number of synthetic peptides and a small molecular antagonist have been generated. Genetically modified animals have been produced for the neuropeptides and receptors. Neuroanatomical, electrophysiological, behavioral and pharmacological characterization of the mutants and transgenic mice uncovered diverse roles of PACAP-PAC1-VAPC2 signaling in peripheral tissues and in the central nervous system. Human genetic studies suggest that the PACAP-PAC1-VPAC2 signaling can be associated with psychiatric illness via mechanisms of not only loss-of-function, but also gain-of-function. For example, a duplication of chromosome 7q36.3 (encoding the VPAC2 receptor) was shown to be associated with schizophrenia, and high levels of PACAP-PAC1 signaling are associated with posttraumatic stress disorder. Whereas knockout animals are appropriate to address loss-of-function of human genetics, transgenic mice overexpressing human transgenes in native environment using artificial chromosomes are particularly valuable and essential to address the consequences of gain-of-function. This review focuses on role of PACAP and PAC1 receptor in brain development, behavior of animals and potential implication in human neurodevelopmental disorders. It also encourages keeping an open mind that alterations of VIP/PACAP signaling may associate with psychiatric illness without overt neuroanatomic changes, and that tuning of VIP/PACAP signaling may represent a novel avenue for the treatment of the psychiatric illness.

PMID: 24220567 [PubMed - indexed for MEDLINE]

Disruption of Mbd5 in mice causes neuronal functional deficits and neurobehavioral abnormalities consistent with 2q23.1 microdeletion syndrome.

July 9, 2014 - 3:33pm

Disruption of Mbd5 in mice causes neuronal functional deficits and neurobehavioral abnormalities consistent with 2q23.1 microdeletion syndrome.

EMBO Mol Med. 2014 Jul 7;

Authors: Camarena V, Cao L, Abad C, Abrams A, Toledo Y, Araki K, Araki M, Walz K, Young JI

Abstract
2q23.1 microdeletion syndrome is characterized by intellectual disability, motor delay, autistic-like behaviors, and a distinctive craniofacial phenotype. All patients carry a partial or total deletion of methyl-CpG-binding domain protein 5 (MBD5), suggesting that haploinsufficiency of this gene is responsible for the phenotype. To confirm this hypothesis and to examine the role of MBD5 in vivo, we have generated and characterized an Mbd5 gene-trap mouse model. Our study indicates that the Mbd5(+/) (GT) mouse model recapitulates most of the hallmark phenotypes observed in 2q23.1 deletion carriers including abnormal social behavior, cognitive impairment, and motor and craniofacial abnormalities. In addition, neuronal cultures uncovered a deficiency in neurite outgrowth. These findings support a causal role of MBD5 in 2q23.1 microdeletion syndrome and suggest a role for MBD5 in neuronal processes. The Mbd5(+/) (GT) mouse model will advance our understanding of the abnormal brain development underlying the emergence of 2q23.1 deletion-associated behavioral and cognitive symptoms.

PMID: 25001218 [PubMed - as supplied by publisher]

Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes.

July 9, 2014 - 3:33pm
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Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes.

Nat Commun. 2013;4:2889

Authors: Lambrot R, Xu C, Saint-Phar S, Chountalos G, Cohen T, Paquet M, Suderman M, Hallett M, Kimmins S

Abstract
Epidemiological studies suggest that a father's diet can influence offspring health. A proposed mechanism for paternal transmission of environmental information is via the sperm epigenome. The epigenome includes heritable information such as DNA methylation. We hypothesize that the dietary supply of methyl donors will alter epigenetic reprogramming in sperm. Here we feed male mice either a folate-deficient or folate-sufficient diet throughout life. Paternal folate deficiency is associated with increased birth defects in the offspring, which include craniofacial and musculoskeletal malformations. Genome-wide DNA methylation analysis and the subsequent functional analysis identify differential methylation in sperm of genes implicated in development, chronic diseases such as cancer, diabetes, autism and schizophrenia. While >300 genes are differentially expressed in offspring placenta, only two correspond to genes with differential methylation in sperm. This model suggests epigenetic transmission may involve sperm histone H3 methylation or DNA methylation and that adequate paternal dietary folate is essential for offspring health.

PMID: 24326934 [PubMed - indexed for MEDLINE]

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