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Role of Metabolic Genes in Blood Arsenic Concentrations of Jamaican Children with and without Autism Spectrum Disorder.

August 8, 2014 - 6:11am

Role of Metabolic Genes in Blood Arsenic Concentrations of Jamaican Children with and without Autism Spectrum Disorder.

Int J Environ Res Public Health. 2014;11(8):7874-7895

Authors: Rahbar MH, Samms-Vaughan M, Ma J, Bressler J, Loveland KA, Ardjomand-Hessabi M, Dickerson AS, Grove ML, Shakespeare-Pellington S, Beecher C, McLaughlin W, Boerwinkle E

Abstract
Arsenic is a toxic metalloid with known adverse effects on human health. Glutathione-S-transferase (GST) genes, including GSTT1, GSTP1, and GSTM1, play a major role in detoxification and metabolism of xenobiotics. We investigated the association between GST genotypes and whole blood arsenic concentrations (BASC) in Jamaican children with and without autism spectrum disorder (ASD). We used data from 100 ASD cases and their 1:1 age- and sex-matched typically developing (TD) controls (age 2-8 years) from Jamaica. Using log-transformed BASC as the dependent variable in a General Linear Model, we observed a significant interaction between GSTP1 and ASD case status while controlling for several confounding variables. However, for GSTT1 and GSTM1 we did not observe any significant associations with BASC. Our findings indicate that TD children who had the Ile/Ile or Ile/Val genotype for GSTP1 had a significantly higher geometric mean BASC than those with genotype Val/Val (3.67 µg/L vs. 2.69 µg/L, p < 0.01). Although, among the ASD cases, this difference was not statistically significant, the direction of the observed difference was consistent with that of the TD control children. These findings suggest a possible role of GSTP1 in the detoxification of arsenic.

PMID: 25101770 [PubMed - as supplied by publisher]

Dysregulated nitric oxide signaling as a candidate mechanism of fragile X syndrome and other neuropsychiatric disorders.

August 8, 2014 - 6:11am

Dysregulated nitric oxide signaling as a candidate mechanism of fragile X syndrome and other neuropsychiatric disorders.

Front Genet. 2014;5:239

Authors: Colvin SM, Kwan KY

Abstract
A mechanistic understanding of the pathophysiology underpinning psychiatric disorders is essential for the development of targeted molecular therapies. For fragile X syndrome (FXS), recent mechanistic studies have been focused on the metabotropic glutamate receptor (mGluR) signaling pathway. This line of research has led to the discovery of promising candidate drugs currently undergoing various phases of clinical trial, and represents a model of how biological insights can inform therapeutic strategies in neurodevelopmental disorders. Although mGluR signaling is a key mechanism at which targeted treatments can be directed, it is likely to be one of many mechanisms contributing to FXS. A more complete understanding of the molecular and neural underpinnings of the disorder is expected to inform additional therapeutic strategies. Alterations in the assembly of neural circuits in the neocortex have been recently implicated in genetic studies of autism and schizophrenia, and may also contribute to FXS. In this review, we explore dysregulated nitric oxide signaling in the developing neocortex as a novel candidate mechanism of FXS. This possibility stems from our previous work demonstrating that neuronal nitric oxide synthase 1 (NOS1 or nNOS) is regulated by the FXS protein FMRP in the mid-fetal human neocortex. Remarkably, in the mid-late fetal and early postnatal neocortex of human FXS patients, NOS1 expression is severely diminished. Given the role of nitric oxide in diverse neural processes, including synaptic development and plasticity, the loss of NOS1 in FXS may contribute to the etiology of the disorder. Here, we outline the genetic and neurobiological data that implicate neocortical dysfunction in FXS, review the evidence supporting dysregulated nitric oxide signaling in the developing FXS neocortex and its contribution to the disorder, and discuss the implications for targeting nitric oxide signaling in the treatment of FXS and other psychiatric illnesses.

PMID: 25101118 [PubMed]

Bias towards large genes in autism.

August 8, 2014 - 6:11am

Bias towards large genes in autism.

Nature. 2014 Aug 7;512(7512):E1-2

Authors: Shohat S, Shifman S

PMID: 25100484 [PubMed - in process]

BDNF in fragile X syndrome.

August 7, 2014 - 8:32am
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BDNF in fragile X syndrome.

Neuropharmacology. 2014 Jan;76 Pt C:729-36

Authors: Castrén ML, Castrén E

Abstract
Fragile X syndrome (FXS) is a monogenic disorder that is caused by the absence of FMR1 protein (FMRP). FXS serves as an excellent model disorder for studies investigating disturbed molecular mechanisms and synapse function underlying cognitive impairment, autism, and behavioral disturbance. Abnormalities in dendritic spines and synaptic transmission in the brain of FXS individuals and mouse models for FXS indicate perturbations in the development, maintenance, and plasticity of neuronal network connectivity. However, numerous alterations are found during the early development in FXS, including abnormal differentiation of neural progenitors and impaired migration of newly born neurons. Several aspects of FMRP function are modulated by brain-derived neurotrophic factor (BDNF) signaling. Here, we review the evidence of the role for BDNF in the developing and adult FXS brain. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

PMID: 23727436 [PubMed - indexed for MEDLINE]

Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression.

August 6, 2014 - 7:35am

Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression.

Mol Psychiatry. 2014 Aug 5;

Authors: Milekic MH, Xin Y, O'Donnell A, Kumar KK, Bradley-Moore M, Malaspina D, Moore H, Brunner D, Ge Y, Edwards J, Paul S, Haghighi FG, Gingrich JA

Abstract
Advanced paternal age (APA) has been shown to be a significant risk factor in the offspring for neurodevelopmental psychiatric disorders, such as schizophrenia and autism spectrum disorders. During aging, de novo mutations accumulate in the male germline and are frequently transmitted to the offspring with deleterious effects. In addition, DNA methylation during spermatogenesis is an active process, which is susceptible to errors that can be propagated to subsequent generations. Here we test the hypothesis that the integrity of germline DNA methylation is compromised during the aging process. A genome-wide DNA methylation screen comparing sperm from young and old mice revealed a significant loss of methylation in the older mice in regions associated with transcriptional regulation. The offspring of older fathers had reduced exploratory and startle behaviors and exhibited similar brain DNA methylation abnormalities as observed in the paternal sperm. Offspring from old fathers also had transcriptional dysregulation of developmental genes implicated in autism and schizophrenia. Our findings demonstrate that DNA methylation abnormalities arising in the sperm of old fathers are a plausible mechanism to explain some of the risks that APA poses to resulting offspring.Molecular Psychiatry advance online publication, 5 August 2014; doi:10.1038/mp.2014.84.

PMID: 25092244 [PubMed - as supplied by publisher]

Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome.

August 5, 2014 - 7:07am
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Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome.

Hum Genet. 2014 Jul;133(7):847-59

Authors: Sarasua SM, Boccuto L, Sharp JL, Dwivedi A, Chen CF, Rollins JD, Rogers RC, Phelan K, DuPont BR

Abstract
This study is the first to describe age-related changes in a large cohort of patients with Phelan-McDermid syndrome (PMS), also known as 22q13 deletion syndrome. Over a follow-up period of up to 12 years, physical examinations and structured interviews were conducted for 201 individuals diagnosed with PMS, 120 patients had a focused, high-resolution 22q12q13 array CGH, and 92 patients' deletions were assessed for parent-of-origin. 22q13 genomic anomalies include terminal deletions of 22q13 (89 %), terminal deletions and interstitial duplications (9 %), and interstitial deletions (2 %). Considering different age groups, in older patients, behavioral problems tended to subside, developmental abilities improved, and some features such as large or fleshy hands, full or puffy eyelids, hypotonia, lax ligaments, and hyperextensible joints were less frequent. However, the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age. Some neurologic and dysmorphic features such as speech and developmental delay and macrocephaly correlated with deletion size. Deletion sizes in more recently diagnosed patients tend to be smaller than those diagnosed a decade earlier. Seventy-three percent of de novo deletions were of paternal origin. Seizures were reported three times more often among patients with a de novo deletion of the maternal rather than paternal chromosome 22. This analysis improves the understanding of the clinical presentation and natural history of PMS and can serve as a reference for the prevalence of clinical features in the syndrome.

PMID: 24481935 [PubMed - indexed for MEDLINE]

Prefrontal cognitive deficits in mice with altered cerebral cortical GABAergic interneurons.

August 5, 2014 - 7:07am
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Prefrontal cognitive deficits in mice with altered cerebral cortical GABAergic interneurons.

Behav Brain Res. 2014 Feb 1;259:143-51

Authors: Bissonette GB, Bae MH, Suresh T, Jaffe DE, Powell EM

Abstract
Alterations of inhibitory GABAergic neurons are implicated in multiple psychiatric and neurological disorders, including schizophrenia, autism and epilepsy. In particular, interneuron deficits in prefrontal areas, along with presumed decreased inhibition, have been reported in several human patients. The majority of forebrain GABAergic interneurons arise from a single subcortical source before migrating to their final regional destination. Factors that govern the interneuron populations have been identified, demonstrating that a single gene mutation may globally affect forebrain structures or a single area. In particular, mice lacking the urokinase plasminogen activator receptor (Plaur) gene have decreased GABAergic interneurons in frontal and parietal, but not caudal, cortical regions. Plaur assists in the activation of hepatocyte growth factor/scatter factor (HGF/SF), and several of the interneuron deficits are correlated with decreased levels of HGF/SF. In some cortical regions, the interneuron deficit can be remediated by endogenous overexpression of HGF/SF. In this study, we demonstrate decreased parvalbumin-expressing interneurons in the medial frontal cortex, but not in the hippocampus or basal lateral amygdala in the Plaur null mouse. The Plaur null mouse demonstrates impaired medial frontal cortical function in extinction of cued fear conditioning and the inability to form attentional sets. Endogenous HGF/SF overexpression increased the number of PV-expressing cells in medial frontal cortical areas to levels greater than found in wildtype mice, but did not remediate the behavioral deficits. These data suggest that proper medial frontal cortical function is dependent upon optimum levels of inhibition and that a deficit or excess of interneuron numbers impairs normal cognition.

PMID: 24211452 [PubMed - indexed for MEDLINE]

Temporal and spectral differences in the ultrasonic vocalizations of fragile X knock out mice during postnatal development.

August 5, 2014 - 7:07am
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Temporal and spectral differences in the ultrasonic vocalizations of fragile X knock out mice during postnatal development.

Behav Brain Res. 2014 Feb 1;259:119-30

Authors: Lai JK, Sobala-Drozdowski M, Zhou L, Doering LC, Faure PA, Foster JA

Abstract
The fmr1 knock out (KO) mouse has been a useful animal model to understand pathology and treatment of FXS, both anatomically and behaviorally. Ultrasonic vocalizations (USVs) are a behavioral tool to assess early life communication deficits in mice. Here, we report on the temporal and spectral features of USVs emitted after maternal separation in wild type (FVB/N) and fmr1 KO pups at postnatal days (P) P4, P7 and P10. The results show changes in the number and duration of calls in fmr1 KO pups and wild type pups were dependent on age and call type. Fmr1 KO pups showed an increased number of USVs at P7 but not at P4 or P10. This increase was specific to Frequency Jump calls. In addition, fmr1 KO mice showed a developmental shift in the temporal distribution of calls, with P10 mice calling in distinct bout patterns. Overall, these findings provide evidence that changes in USV outcomes were specific to certain call types and ages in fmr1 KO mice. Because early postnatal life is a window during which multiple neural systems activate and become established, behavioral measures such as using USVs as a measure of communication, may be useful as a predictor of brain changes and later developmental behavioral changes. Work is needed to better understand the functional outcomes of altered development of USVs and how these changes contribute to later emergence of autistic-like behaviors in animal models of autism.

PMID: 24211451 [PubMed - indexed for MEDLINE]

Repetitive behavior profile and supersensitivity to amphetamine in the C58/J mouse model of autism.

August 5, 2014 - 7:07am
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Repetitive behavior profile and supersensitivity to amphetamine in the C58/J mouse model of autism.

Behav Brain Res. 2014 Feb 1;259:200-14

Authors: Moy SS, Riddick NV, Nikolova VD, Teng BL, Agster KL, Nonneman RJ, Young NB, Baker LK, Nadler JJ, Bodfish JW

Abstract
Restricted repetitive behaviors are core symptoms of autism spectrum disorders (ASDs). The range of symptoms encompassed by the repetitive behavior domain includes lower-order stereotypy and self-injury, and higher-order indices of circumscribed interests and cognitive rigidity. Heterogeneity in clinical ASD profiles suggests that specific manifestations of repetitive behavior reflect differential neuropathology. The present studies utilized a set of phenotyping tasks to determine a repetitive behavior profile for the C58/J mouse strain, a model of ASD core symptoms. In an observational screen, C58/J demonstrated overt motor stereotypy, but not over-grooming, a commonly-used measure for mouse repetitive behavior. Amphetamine did not exacerbate motor stereotypy, but had enhanced stimulant effects on locomotion and rearing in C58/J, compared to C57BL/6J. Both C58/J and Grin1 knockdown mice, another model of ASD-like behavior, had marked deficits in marble-burying. In a nose poke task for higher-order repetitive behavior, C58/J had reduced holeboard exploration and preference for non-social, versus social, olfactory stimuli, but did not demonstrate cognitive rigidity following familiarization to an appetitive stimulus. Analysis of available high-density genotype data indicated specific regions of divergence between C58/J and two highly-sociable strains with common genetic lineage. Strain genome comparisons identified autism candidate genes, including Cntnap2 and Slc6a4, located within regions divergent in C58/J. However, Grin1, Nlgn1, Sapap3, and Slitrk5, genes linked to repetitive over-grooming, were not in regions of divergence. These studies suggest that specific repetitive phenotypes can be used to distinguish ASD mouse models, with implications for divergent underlying mechanisms for different repetitive behavior profiles.

PMID: 24211371 [PubMed - indexed for MEDLINE]

SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth.

August 5, 2014 - 7:07am
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SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth.

Hum Mol Genet. 2014 Jan 1;23(1):90-103

Authors: Corradi A, Fadda M, Piton A, Patry L, Marte A, Rossi P, Cadieux-Dion M, Gauthier J, Lapointe L, Mottron L, Valtorta F, Rouleau GA, Fassio A, Benfenati F, Cossette P

Abstract
An increasing number of genes predisposing to autism spectrum disorders (ASDs) has been identified, many of which are implicated in synaptic function. This 'synaptic autism pathway' notably includes disruption of SYN1 that is associated with epilepsy, autism and abnormal behavior in both human and mice models. Synapsins constitute a multigene family of neuron-specific phosphoproteins (SYN1-3) present in the majority of synapses where they are implicated in the regulation of neurotransmitter release and synaptogenesis. Synapsins I and II, the major Syn isoforms in the adult brain, display partially overlapping functions and defects in both isoforms are associated with epilepsy and autistic-like behavior in mice. In this study, we show that nonsense (A94fs199X) and missense (Y236S and G464R) mutations in SYN2 are associated with ASD in humans. The phenotype is apparent in males. Female carriers of SYN2 mutations are unaffected, suggesting that SYN2 is another example of autosomal sex-limited expression in ASD. When expressed in SYN2  knockout neurons, wild-type human Syn II fully rescues the SYN2 knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants are virtually unable to modify the SYN2 knockout phenotype. These results identify for the first time SYN2  as a novel predisposing gene for ASD and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies ASD.

PMID: 23956174 [PubMed - indexed for MEDLINE]

Diagnostic yield of array comparative genomic hybridization in adults with autism spectrum disorders.

August 5, 2014 - 7:07am
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Diagnostic yield of array comparative genomic hybridization in adults with autism spectrum disorders.

Genet Med. 2014 Jan;16(1):70-7

Authors: Stobbe G, Liu Y, Wu R, Hudgings LH, Thompson O, Hisama FM

Abstract
PURPOSE: Array comparative genomic hybridization is available for the evaluation of autism spectrum disorders. The diagnostic yield of testing is 5-18% in children with developmental disabilities, including autism spectrum disorders and multiple congenital anomalies. The yield of array comparative genomic hybridization in the adult autism spectrum disorder population is unknown.
METHODS: We performed a retrospective chart review for 40 consecutive patients referred for genetic evaluation of autism from July 2009 through April 2012. Four pediatric patients were excluded. Medical history and prior testing were reviewed. Clinical genetic evaluation and testing were offered to all patients.
RESULTS: The study population comprised 36 patients (age range 18-45, mean 25.3 years). An autism spectrum disorder diagnosis was confirmed in 34 of 36 patients by medical record review. One patient had had an abnormal karyotype; none had prior array comparative genomic hybridization testing. Of the 23 patients with autism who underwent array comparative genomic hybridization, 2 of 23 (8.7%) had pathogenic or presumed pathogenic abnormalities and 2 of 23 (8.7%) had likely pathogenic copy-number variants. An additional 5 of 23 (22%) of autism patients had variants of uncertain significance without subclassification.
CONCLUSION: Including one patient newly diagnosed with fragile X syndrome, our data showed abnormal or likely pathogenic findings in 5 of 24 (21%) adult autism patients. Genetic reevaluation in adult autism patients is warranted.

PMID: 23765050 [PubMed - indexed for MEDLINE]

Screening of NLGN3 and NLGN4X genes in Thai children with autism spectrum disorder.

August 2, 2014 - 6:02am
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Screening of NLGN3 and NLGN4X genes in Thai children with autism spectrum disorder.

Psychiatr Genet. 2014 Feb;24(1):42-3

Authors: Mikhailov A, Fennell A, Plong-on O, Sripo T, Hansakunachai T, Roongpraiwan R, Sombuntham T, Ruangdaraganon N, Vincent JB, Limprasert P

PMID: 24362370 [PubMed - indexed for MEDLINE]

Association between ASMT and autistic-like traits in children from a Swedish nationwide cohort.

August 2, 2014 - 6:02am
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Association between ASMT and autistic-like traits in children from a Swedish nationwide cohort.

Psychiatr Genet. 2014 Feb;24(1):21-7

Authors: Jonsson L, Anckarsäter H, Zettergren A, Westberg L, Walum H, Lundström S, Larsson H, Lichtenstein P, Melke J

Abstract
Individuals with autism spectrum disorders often show low levels of melatonin, and it has been suggested that this decrease may be because of the low activity of the acetylserotonin O-methyltransferase (ASMT), the last enzyme in the melatonin-synthesis pathway. Also, genetic variants in ASMT have been associated with autism, as well as with low ASMT activity and melatonin levels, suggesting that the low ASMT activity observed in autism may partly be because of variations within the ASMT gene. In this study, we present a symptom-based approach to investigate possible associations between ASMT and autistic-like traits in the general population. To this end, continuous measures of autistic-like traits were assessed in a nationally representative twin cohort (n=1771) from Sweden and six single nucleotide polymorphisms (SNPs), and a duplication of exons 2-8 in ASMT were genotyped. Our results show a nominally significant association, in girls, between one single nucleotide polymorphism (rs5949028) in the last intron of ASMT and social interaction impairments. No significant association, however, was observed with traits related to language impairment or restricted and repetitive behavior. In conclusion, our results support the possible involvement of the ASMT gene in autism spectrum disorders, and our finding that only one of the three traits shows association suggests that genetic research may benefit from adopting a symptom-specific approach to identify genes involved in autism psychopathology.

PMID: 23995775 [PubMed - indexed for MEDLINE]

A proof-of-concept study: exon-level expression profiling and alternative splicing in autism using lymphoblastoid cell lines.

August 2, 2014 - 6:02am
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A proof-of-concept study: exon-level expression profiling and alternative splicing in autism using lymphoblastoid cell lines.

Psychiatr Genet. 2014 Feb;24(1):1-9

Authors: Talebizadeh Z, Aldenderfer R, Wen Chen X

Abstract
OBJECTIVE: Autism is a complex, heterogeneous neurobehavioral disorder with many causes and varying degrees of severity. Some genetic implications related to autism may involve gene-regulatory processes such as alternative splicing. Here, we assess the feasibility of profiling exon-level gene expression in autism using the Affymetrix Human exon 1.0 ST array.
METHODS: We examined lymphoblastoid cell line-derived RNAs from five patients with autism compared with five controls.
RESULTS: Analysis of variance and Bonferroni multiple test correction identified 57 genes exhibiting differential exon-level expression, suggesting potential changes in the resultant alternatively spliced transcripts in autism compared with controls. Genes with differentially expressed exons included CYFIP1, a previously reported autism susceptibility gene. Furthermore, several genes recently reported to have deregulated alternative splicing in autism brain samples showed differential exon expression in our autism group.
CONCLUSION: The paucity of autism brain samples and extensive phenotypic heterogeneity of autism demands finding ways to also identify autism-related genomic events in accessible nonbrain resources, which may contribute in biomarker identifications. This proof-of-concept study shows that the analysis of alternative splicing in lymphoblastoid cell line samples has a potential to reveal at least a subset of brain-related deregulation of splicing machinery that might be implicated in autism.

PMID: 23838881 [PubMed - indexed for MEDLINE]

Delineating the 15q13.3 microdeletion phenotype: a case series and comprehensive review of the literature.

August 1, 2014 - 8:16am

Delineating the 15q13.3 microdeletion phenotype: a case series and comprehensive review of the literature.

Genet Med. 2014 Jul 31;

Authors: Lowther C, Costain G, Stavropoulos DJ, Melvin R, Silversides CK, Andrade DM, So J, Faghfoury H, Lionel AC, Marshall CR, Scherer SW, Bassett AS

Abstract
Purpose:Recurrent 15q13.3 deletions are enriched in multiple neurodevelopmental conditions including intellectual disability, autism, epilepsy, and schizophrenia. However, the 15q13.3 microdeletion syndrome remains ill-defined.Methods:We systematically compiled all cases of 15q13.3 deletion published before 2014. We also examined three locally available cohorts to identify new adults with 15q13.3 deletions.Results:We identified a total of 246 cases (133 children, 113 adults) with deletions overlapping or within the 15q13.3 (breakpoint (BP)4-BP5) region, including seven novel adult cases from local cohorts. No BP4-BP5 deletions were identified in 23,838 adult controls. Where known, 15q13.3 deletions were typically inherited (85.4%) and disproportionately of maternal origin (P < 0.0001). Overall, 198 cases (121 children, 77 adults; 80.5%) had at least one neuropsychiatric diagnosis. Accounting for ascertainment, developmental disability/intellectual disability was present in 57.7%, epilepsy/seizures in 28.0%, speech problems in 15.9%, autism spectrum disorder in 10.9%, schizophrenia in 10.2%, mood disorder in 10.2%, and attention deficit hyperactivity disorder in 6.5%. By contrast, major congenital malformations, including congenital heart disease (2.4%), were uncommon. Placenta previa occurred in the pregnancies of four cases.Conclusion:The 15q13.3 microdeletion syndrome is predominantly characterized by neuropsychiatric expression. There are implications for pre- and postnatal detection, genetic counseling, and anticipatory care.Genet Med advance online publication 31 July 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.83.

PMID: 25077648 [PubMed - as supplied by publisher]

Brain region-specific methylation in the promoter of the murine oxytocin receptor gene is involved in its expression regulation.

August 1, 2014 - 8:16am
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Brain region-specific methylation in the promoter of the murine oxytocin receptor gene is involved in its expression regulation.

Psychoneuroendocrinology. 2014 Jan;39:121-31

Authors: Harony-Nicolas H, Mamrut S, Brodsky L, Shahar-Gold H, Barki-Harrington L, Wagner S

Abstract
Oxytocin is a nine amino acid neuropeptide that is known to play a critical role in fetal expulsion and breast-feeding, and has been recently implicated in mammalian social behavior. The actions of both central and peripheral oxytocin are mediated through the oxytocin receptor (Oxtr), which is encoded by a single gene. In contrast to the highly conserved expression of oxytocin in specific hypothalamic nuclei, the expression of its receptor in the brain is highly diverse among different mammalian species or even within individuals of the same species. The diversity in the pattern of brain Oxtr expression among mammals is thought to contribute to the broad range of social systems and organizations. Yet, the mechanisms underlying this diversity are poorly understood. DNA methylation is a major epigenetic mechanism that regulates gene transcription, and has been linked to reduced expression levels of the Oxtr in individuals with autism. Here we hypothesize that DNA methylation is involved in the expression regulation of Oxtr in the mouse brain. By combining bisulfite DNA conversion and Next-Generation Sequencing we found that specific CpG sites are differentially methylated between distinct brain regions expressing different levels of Oxtr mRNA. Some of these CpG sites are located within putative binding sites of transcription factors known to regulate Oxtr expression, including estrogen receptor α (ERα) and SP1. Specifically, methylation of the SP1 site was found to positively correlate with Oxtr expression. Furthermore, we revealed that the methylation levels of these sites in the various brain regions predict the relationship between ERα and Oxtr mRNA levels. Collectively, our results suggest that brain region-specific expression of the mouse Oxtr gene is epigenetically regulated by DNA methylation of its promoter.

PMID: 24275011 [PubMed - indexed for MEDLINE]

Genetic counseling for susceptibility loci and neurodevelopmental disorders: the del15q11.2 as an example.

August 1, 2014 - 8:16am
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Genetic counseling for susceptibility loci and neurodevelopmental disorders: the del15q11.2 as an example.

Am J Med Genet A. 2013 Nov;161A(11):2846-54

Authors: De Wolf V, Brison N, Devriendt K, Peeters H

Abstract
In recent years, several recurrent copy number variations (CNVs) that confer risk of neurodevelopmental disorders have been identified (e.g., del and dup 16p11.2, del15q13.3, del and dup 1q21.1, del16p13.3, del15q11.2). They are often inherited from an unaffected parent and lack phenotypic specificity. Although there is growing evidence from association studies to consider them as susceptibility CNVs, their clinical utility is debated. Yet the clinician is frequently challenged to deal with these counseling situations without guidelines or consensus. In this report, counseling issues and research opportunities are discussed, with the recurrent 15q11.2 BP1-BP2 (including CYFIP1, NIPA1, NIPA2, TUBGCP5) as an example. Several clinical reports have been published describing patients with del15q11.2 featuring intellectual disability, developmental delay, neurological problems, autism spectrum disorder (ASD), attention problems, speech delay, and dysmorphism. The del15q11.2 was found to be significantly associated with intellectual disability, schizophrenia, epilepsy, and ASD. In this report we discuss how patient-specific and family-specific information may alter the interpretation of del15q11.2 as a contributing factor to the disorder in practical counseling situations. In addition, an association study for ASD in a Belgian Flemish cohort and an overview of reported association studies, clinical reports and genomics data for del15q11.2 are presented.

PMID: 24123946 [PubMed - indexed for MEDLINE]

Fragile X syndrome: From protein function to therapy.

August 1, 2014 - 8:16am
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Fragile X syndrome: From protein function to therapy.

Am J Med Genet A. 2013 Nov;161A(11):2809-21

Authors: Bagni C, Oostra BA

Abstract
Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and autism. The FMR1 gene contains a CGG repeat present in the 5'-untranslated region which can be unstable upon transmission to the next generation. The repeat is up to 55 CGGs long in the normal population. In patients with fragile X syndrome (FXS), a repeat length exceeding 200 CGGs generally leads to methylation of the repeat and the promoter region, which is accompanied by silencing of the FMR1 gene. The disease is a result of lack of expression of the fragile X mental retardation protein leading to severe symptoms, including intellectual disability, hyperactivity, and autistic-like behavior. The FMR1 protein (FMRP) has a number of functions. The translational dysregulation of a subset of mRNAs targeted by FMRP is probably the major contribution to FXS. FMRP is also involved in mRNA transport to synapses where protein synthesis occurs. For some FMRP-bound mRNAs, FMRP is a direct modulator of mRNA stability either by sustaining or preventing mRNA decay. Increased knowledge about the role of FMRP has led to the identification of potential treatments for fragile X syndrome that were often tested first in the different animal models. This review gives an overview about the present knowledge of the function of FMRP and the therapeutic strategies in mouse and man.

PMID: 24115651 [PubMed - indexed for MEDLINE]

Extrarenal roles of the with-no-lysine[K] kinases (WNKs).

August 1, 2014 - 8:16am
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Extrarenal roles of the with-no-lysine[K] kinases (WNKs).

Clin Exp Pharmacol Physiol. 2013 Dec;40(12):885-94

Authors: Siew K, O'Shaughnessy KM

Abstract
Identified over a decade ago, the with-no-lysine[K] kinases (WNKs) have been the subsequent focus of intense research into the renal handling of Na(+) , Cl(-) and K(+) and several rare monogenetic diseases. However, the potential extrarenal roles for WNKs have been less well explored. Thiazides and Gordon syndrome are known to have effects on bone mineral density, Ca(2+) and PO4 (3-) homeostasis, which were originally assumed to be an indirect effect through the kidney. However, current data suggest a complex and direct role for WNKs in the physiology of bone. The WNKs also modulate systemic blood pressure at several levels, including the vascular resistance vessels, where they cause vasoconstriction by altering the abundance of the transient receptor potential canonical channel 3 and/or phosphorylation of the Na(+) -K(+) -2Cl(-) cotransporter 1 in vascular smooth muscle cells. The WNKs and many of the cation-coupled Cl(-) cotransporters they regulate are highly expressed in the central nervous system and recent work suggests that WNK dysfunction may have a role in the development of autism, schizophrenia and hereditary sensory and autonomic neuropathy Type 2. Finally, the WNK-sterile 20 kinase signalling axis represents an evolutionarily ancient mechanism for maintaining osmotic homeostasis, but a rapidly expanding body of evidence also shows a role in immunity and cellular regulation.

PMID: 23662678 [PubMed - indexed for MEDLINE]

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability.

July 31, 2014 - 8:06am

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability.

Eur J Hum Genet. 2014 Jul 30;

Authors: Vergult S, Dheedene A, Meurs A, Faes F, Isidor B, Janssens S, Gautier A, Le Caignec C, Menten B

Abstract
Voltage-gated calcium channels have an important role in neurotransmission. Aberrations affecting genes encoding the alpha subunit of these channels have been associated with epilepsy and neuropsychiatric disorders such as autism or schizophrenia. Here we report three patients with a genomic aberration affecting the CACNA2D1 gene encoding the α2δ subunit of these voltage-gated calcium channels. All three patients present with epilepsy and intellectual disability pinpointing the CACNA2D1 gene as an interesting candidate gene for these clinical features. Besides these characteristics, patient 2 also presents with obesity with hyperinsulinism, which is very likely to be caused by deletion of the CD36 gene.European Journal of Human Genetics advance online publication, 30 July 2014; doi:10.1038/ejhg.2014.141.

PMID: 25074461 [PubMed - as supplied by publisher]

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