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Transient DNMT1 suppression reveals hidden heritable marks in the genome.

June 19, 2015 - 8:01am
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Transient DNMT1 suppression reveals hidden heritable marks in the genome.

Nucleic Acids Res. 2015 Feb 18;43(3):1485-97

Authors: McGraw S, Zhang JX, Farag M, Chan D, Caron M, Konermann C, Oakes CC, Mohan KN, Plass C, Pastinen T, Bourque G, Chaillet JR, Trasler JM

Abstract
Genome-wide demethylation and remethylation of DNA during early embryogenesis is essential for development. Imprinted germline differentially methylated domains (gDMDs) established by sex-specific methylation in either male or female germ cells, must escape these dynamic changes and sustain precise inheritance of both methylated and unmethylated parental alleles. To identify other, gDMD-like sequences with the same epigenetic inheritance properties, we used a modified embryonic stem (ES) cell line that emulates the early embryonic demethylation and remethylation waves. Transient DNMT1 suppression revealed gDMD-like sequences requiring continuous DNMT1 activity to sustain a highly methylated state. Remethylation of these sequences was also compromised in vivo in a mouse model of transient DNMT1 loss in the preimplantation embryo. These novel regions, possessing heritable epigenetic features similar to imprinted-gDMDs are required for normal physiological and developmental processes and when disrupted are associated with disorders such as cancer and autism spectrum disorders. This study presents new perspectives on DNA methylation heritability during early embryo development that extend beyond conventional imprinted-gDMDs.

PMID: 25578964 [PubMed - indexed for MEDLINE]

Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro.

June 19, 2015 - 8:01am
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Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro.

J Neurochem. 2015 May;133(4):532-43

Authors: Fan LW, Bhatt A, Tien LT, Zheng B, Simpson KL, Lin RC, Cai Z, Kumar P, Pang Y

Abstract
Serotonin (5-hydroxytryptamine, 5-HT) has been implicated to play critical roles in early neural development. Recent reports have suggested that perinatal exposure to selective serotonin reuptake inhibitors (SSRIs) resulted in cortical network miswiring, abnormal social behavior, callosal myelin malformation, as well as oligodendrocyte (OL) pathology in rats. To gain further insight into the cellular and molecular mechanisms underlying SSRIs-induced OL and myelin abnormalities, we investigated the effect of 5-HT exposure on OL development, cell death, and myelination in cell culture models. First, we showed that 5-HT receptor 1A and 2A subtypes were expressed in OL lineages, using immunocytochemistry, Western blot, as well as intracellular Ca(2+) measurement. We then assessed the effect of serotonin exposure on the lineage development, expression of myelin proteins, cell death, and myelination, in purified OL and neuron-OL myelination cultures. For pure OL cultures, our results showed that 5-HT exposure led to disturbance of OL development, as indicated by aberrant process outgrowth and reduced myelin proteins expression. At higher doses, such exposure triggered a development-dependent cell death, as immature OLs exhibited increasing susceptibility to 5-HT treatment compared to OL progenitor cells (OPC). We showed further that 5-HT-induced immature OL death was mediated at least partially via 5-HT2A receptor, since cell death could be mimicked by 5-HT2A receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride, (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride, but atten-uated by pre-treatment with 5-HT2A receptor antagonist ritanserin. Utilizing a neuron-OL myelination co-culture model, our data showed that 5-HT exposure significantly reduced the number of myelinated internodes. In contrast to cell injury observed in pure OL cultures, 5-HT exposure did not lead to OL death or reduced OL density in neuron-OL co-cultures. However, abnormal patterns of contactin-associated protein (Caspr) clustering were observed at the sites of Node of Ranvier, suggesting that 5-HT exposure may affect other axon-derived factors for myelination. In summary, this is the first study to demonstrate that manipulation of serotonin levels affects OL development and myelination, which may contribute to altered neural connectivity noted in SSRIs-treated animals. The current in vitro study demonstrated that exposure to high level of serotonin (5-HT) led to aberrant oligodendrocyte (OL) development, cell injury, and myelination deficit. We propose that elevated extracellular serotonin levels in the fetal brain, such as upon the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, may adversely affect OL development and/or myelination, thus contributing to altered neural connectivity seen in Autism Spectrum Disorders. OPC = oligodendrocyte progenitor cell.

PMID: 25382136 [PubMed - indexed for MEDLINE]

A novel ribosomopathy caused by dysfunction of RPL10 disrupts neurodevelopment and causes X-linked microcephaly in humans.

June 18, 2015 - 6:23am
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A novel ribosomopathy caused by dysfunction of RPL10 disrupts neurodevelopment and causes X-linked microcephaly in humans.

Genetics. 2014 Oct;198(2):723-33

Authors: Brooks SS, Wall AL, Golzio C, Reid DW, Kondyles A, Willer JR, Botti C, Nicchitta CV, Katsanis N, Davis EE

Abstract
Neurodevelopmental defects in humans represent a clinically heterogeneous group of disorders. Here, we report the genetic and functional dissection of a multigenerational pedigree with an X-linked syndromic disorder hallmarked by microcephaly, growth retardation, and seizures. Using an X-linked intellectual disability (XLID) next-generation sequencing diagnostic panel, we identified a novel missense mutation in the gene encoding 60S ribosomal protein L10 (RPL10), a locus associated previously with autism spectrum disorders (ASD); the p.K78E change segregated with disease under an X-linked recessive paradigm while, consistent with causality, carrier females exhibited skewed X inactivation. To examine the functional consequences of the p.K78E change, we modeled RPL10 dysfunction in zebrafish. We show that endogenous rpl10 expression is augmented in anterior structures, and that suppression decreases head size in developing morphant embryos, concomitant with reduced bulk translation and increased apoptosis in the brain. Subsequently, using in vivo complementation, we demonstrate that p.K78E is a loss-of-function variant. Together, our findings suggest that a mutation within the conserved N-terminal end of RPL10, a protein in close proximity to the peptidyl transferase active site of the 60S ribosomal subunit, causes severe defects in brain formation and function.

PMID: 25316788 [PubMed - indexed for MEDLINE]

Opposite risk patterns for autism and schizophrenia are associated with normal variation in birth size: phenotypic support for hypothesized diametric gene-dosage effects.

June 18, 2015 - 6:23am
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Opposite risk patterns for autism and schizophrenia are associated with normal variation in birth size: phenotypic support for hypothesized diametric gene-dosage effects.

Proc Biol Sci. 2014 Nov 7;281(1794):20140604

Authors: Byars SG, Stearns SC, Boomsma JJ

Abstract
Opposite phenotypic and behavioural traits associated with copy number variation and disruptions to imprinted genes with parent-of-origin effects have led to the hypothesis that autism and schizophrenia share molecular risk factors and pathogenic mechanisms, but a direct phenotypic comparison of how their risks covary has not been attempted. Here, we use health registry data collected on Denmark's roughly 5 million residents between 1978 and 2009 to detect opposing risks of autism and schizophrenia depending on normal variation (mean ± 1 s.d.) in adjusted birth size, which we use as a proxy for diametric gene-dosage variation in utero. Above-average-sized babies (weight, 3691-4090 g; length, 52.8-54.3 cm) had significantly higher risk for autism spectrum (AS) and significantly lower risk for schizophrenia spectrum (SS) disorders. By contrast, below-average-sized babies (2891-3290 g; 49.7-51.2 cm) had significantly lower risk for AS and significantly higher risk for SS disorders. This is the first study directly comparing autism and schizophrenia risks in the same population, and provides the first large-scale empirical support for the hypothesis that diametric gene-dosage effects contribute to these disorders. Only the kinship theory of genomic imprinting predicts the opposing risk patterns that we discovered, suggesting that molecular research on mental disease risk would benefit from considering evolutionary theory.

PMID: 25232142 [PubMed - indexed for MEDLINE]

High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders.

June 17, 2015 - 7:35am

High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders.

Hum Genet. 2015 Jun 16;

Authors: Yavarna T, Al-Dewik N, Al-Mureikhi M, Ali R, Al-Mesaifri F, Mahmoud L, Shahbeck N, Lakhani S, AlMulla M, Nawaz Z, Vitazka P, Alkuraya FS, Ben-Omran T

Abstract
Clinical exome sequencing (CES) has become an increasingly popular diagnostic tool in patients with heterogeneous genetic disorders, especially in those with neurocognitive phenotypes. Utility of CES in consanguineous populations has not yet been determined on a large scale. A clinical cohort of 149 probands from Qatar with suspected Mendelian, mainly neurocognitive phenotypes, underwent CES from July 2012 to June 2014. Intellectual disability and global developmental delay were the most common clinical presentations but our cohort displayed other phenotypes, such as epilepsy, dysmorphism, microcephaly and other structural brain anomalies and autism. A pathogenic or likely pathogenic mutation, including pathogenic CNVs, was identified in 89 probands for a diagnostic yield of 60 %. Consanguinity and positive family history predicted a higher diagnostic yield. In 5 % (7/149) of cases, CES implicated novel candidate disease genes (MANF, GJA9, GLG1, COL15A1, SLC35F5, MAGE4, NEUROG1). CES uncovered two coexisting genetic disorders in 4 % (6/149) and actionable incidental findings in 2 % (3/149) of cases. Average time to diagnosis was reduced from 27 to 5 months. CES, which already has the highest diagnostic yield among all available diagnostic tools in the setting of Mendelian disorders, appears to be particularly helpful diagnostically in the highly consanguineous Middle Eastern population.

PMID: 26077850 [PubMed - as supplied by publisher]

Detection of Chromosomal Aberrations in Clinical Practice: From Karyotype to Genome Sequence.

June 17, 2015 - 7:35am

Detection of Chromosomal Aberrations in Clinical Practice: From Karyotype to Genome Sequence.

Annu Rev Genomics Hum Genet. 2015 May 6;

Authors: Martin CL, Warburton D

Abstract
Since the inception of clinical cytogenetics in the late 1950s, the field has witnessed the evolution of multiple methodologies for the evaluation of chromosomal imbalances and rearrangements. From the replacement of solidly stained chromosomes by Giemsa banding (G-banding) to in situ hybridization and microarrays, each technique has sought to detect smaller and smaller chromosomal aberrations across the genome. Microarray analysis has revealed that copy-number variants-a class of mutation resulting from the loss (deletion) or gain (duplication) of genomic material that is >1 kb in size-are among the significant contributors to human disease and normal variation. Here, we evaluate the history and utility of various methodologies and their impact on the current practice of clinical cytogenetics. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 16 is August 31, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

PMID: 26077817 [PubMed - as supplied by publisher]

Disrupted intricacy of histone H3K4 methylation in neurodevelopmental disorders.

June 17, 2015 - 7:35am

Disrupted intricacy of histone H3K4 methylation in neurodevelopmental disorders.

Epigenomics. 2015 Jun;7(3):503-19

Authors: Vallianatos CN, Iwase S

Abstract
Methylation of histone H3 lysine 4 (H3K4me) is an intricately regulated posttranslational modification, which is broadly associated with enhancers and promoters of actively transcribed genomic loci. Recent advances in next-generation sequencing have identified a number of H3K4me regulators mutated in neurodevelopmental disorders including intellectual disabilities, autism spectrum disorders, and schizophrenia. Here, we aim to summarize the molecular function of H3K4me-regulating enzymes in brain development and function. We describe four H3K4me methyltransferases (KMT2A, KMT2C, KMT2D, KMT2F), four demethylases (KDM1A, KDM5A, KDM5B, KDM5C), and two reader proteins (PHF21A, PHF8) mutated in neurodevelopmental disorders. Understanding the role of these chromatin regulators in the development and maintenance of neural connections will advance therapeutic opportunities for prevention and treatment of these lifelong neurodevelopmental disorders.

PMID: 26077434 [PubMed - in process]

An update on the epigenetics of psychotic diseases and autism.

June 17, 2015 - 7:35am

An update on the epigenetics of psychotic diseases and autism.

Epigenomics. 2015 Jun;7(3):427-49

Authors: Abdolmaleky HM, Zhou JR, Thiagalingam S

Abstract
The examination of potential roles of epigenetic alterations in the pathogenesis of psychotic diseases have become an essential alternative in recent years as genetic studies alone are yet to uncover major gene(s) for psychosis. Here, we describe the current state of knowledge from the gene-specific and genome-wide studies of postmortem brain and blood cells indicating that aberrant DNA methylation, histone modifications and dysregulation of micro-RNAs are linked to the pathogenesis of mental diseases. There is also strong evidence supporting that all classes of psychiatric drugs modulate diverse features of the epigenome. While comprehensive environmental and genetic/epigenetic studies are uncovering the origins, and the key genes/pathways affected in psychotic diseases, characterizing the epigenetic effects of psychiatric drugs may help to design novel therapies in psychiatry.

PMID: 26077430 [PubMed - in process]

Altered expression levels of neurodevelopmental proteins in fetal brains of BTBR T+tf/J mice with autism-like behavioral characteristics.

June 17, 2015 - 7:35am
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Altered expression levels of neurodevelopmental proteins in fetal brains of BTBR T+tf/J mice with autism-like behavioral characteristics.

J Toxicol Environ Health A. 2015;78(8):516-23

Authors: Hwang SR, Kim CY, Shin KM, Jo JH, Kim HA, Heo Y

Abstract
Autism is a brain developmental disorder with characteristics of social interaction defects, language and communication dysfunction, and repetitive behavior. Occurrence of autism is continuously increasing, but the cause of autism is not clearly defined. Genetic linkage or environmental factors were proposed as sources for pathogenesis of autism. BTBR T+tf/J (BTBR) mice were reported as an appropriate animal model for autism investigation because of their similarities in behavioral abnormalities with human autistic subjects. The aim of this study was to evaluate expression levels of proteins involved with brain development at fetal stage of BTBR mice. FVB/NJ mice were used as a control strain because of their social behaviors. Level of fetal brain immunoglobulin (Ig) G deposit was also evaluated. Fetal brains were obtained at d 18 of gestational period. Thirty-one and 27 fetuses were obtained from 3 pregnant BTBR and FVB dams, respectively. The level of glial fibrillary acidic protein expression was significantly lower in fetal brains of BTBR than FVB/NJ mice. Expression of brain-derived neurotrophic factor and myelin basic protein was significantly more upregulated in BTBR than in FVB/NJ mice. No significant difference was obtained for nerve growth factor between the two strains. Levels of IgG isotypes deposited in fetal brain of BTBR mice were significantly higher than in FVB mice except for IgG1. Overall, these results suggest that prenatal alterations in expression of various fetal brain proteins may be implicated in aberrant behavioral characteristics of BTBR mice.

PMID: 25849768 [PubMed - indexed for MEDLINE]

Anxiety, hyperactivity and stereotypy in a zebrafish model of fragile X syndrome and autism spectrum disorder.

June 17, 2015 - 7:35am
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Anxiety, hyperactivity and stereotypy in a zebrafish model of fragile X syndrome and autism spectrum disorder.

Prog Neuropsychopharmacol Biol Psychiatry. 2014 Dec 3;55:40-9

Authors: Kim L, He L, Maaswinkel H, Zhu L, Sirotkin H, Weng W

Abstract
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and is caused by a loss of function of the fragile X mental retardation (fmr1) gene. Animal fmr1-knockout (KO) models are not only of interest for the study of FXS, but have also important implications for our understanding of autism spectrum disorder (ASD). Here we report the behavioral changes in fmr1-knockout zebrafish in an open field with two white and two transparent walls. The neophobic responses that in wild-type (WT) zebrafish normally occur during the first 5-10 min in an unfamiliar environment (such as freezing, hypo-activity and preferences for the bottom and opaque walls of the tank), were weakened in fmr1 mutants, suggesting a reduction of novelty-induced anxiety. The fmr1-KO zebrafish showed somewhat increased vertical activity beyond the 'neophobic phase', but no overall hyperactivity. The mutants demonstrated a clear habituation-independent preference for the transparent walls. Whether this was attributable to altered spatial information processing or to reduced avoidance of open spaces is discussed. Finally, since restrictive repetitive (or stereotypical) behaviors are frequently present in FXS and ASD patients, we analyzed relative turning angles, directional and preferential turning ratios and performed frequency-domain analysis. However, no indications of abnormal movement patterning were detected. The possible reasons for the absence of stereotypical behaviors are discussed in terms of behavioral endpoint selection and of eliciting conditions. Overall, our findings are consistent with those reported in fmr1-KO mice and suggest that further analysis of the fmr1-KO zebrafish model has potential to deepen our understanding of FXS and ASD.

PMID: 24681195 [PubMed - indexed for MEDLINE]

Discovery of highly selective brain-penetrant vasopressin 1a antagonists for the potential treatment of autism via a chemogenomic and scaffold hopping approach.

June 16, 2015 - 6:42am
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Discovery of highly selective brain-penetrant vasopressin 1a antagonists for the potential treatment of autism via a chemogenomic and scaffold hopping approach.

J Med Chem. 2015 Mar 12;58(5):2275-89

Authors: Ratni H, Rogers-Evans M, Bissantz C, Grundschober C, Moreau JL, Schuler F, Fischer H, Alvarez Sanchez R, Schnider P

Abstract
From a micromolar high throughput screening hit 7, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable tool compounds which demonstrated a V1a mediated central in vivo effect. This novel series was further optimized through parallel synthesis with a focus on balancing lipophilicity to achieve robust aqueous solubility while avoiding P-gp mediated efflux. These efforts led to the discovery of the highly potent and selective brain-penetrant hV1a antagonist RO5028442 (8) suitable for human clinical studies in people with autism.

PMID: 25654260 [PubMed - indexed for MEDLINE]

Measuring quantitative autism traits in families: informant effect or intergenerational transmission?

June 16, 2015 - 6:42am
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Measuring quantitative autism traits in families: informant effect or intergenerational transmission?

Eur Child Adolesc Psychiatry. 2015 Apr;24(4):385-95

Authors: De la Marche W, Noens I, Kuppens S, Spilt JL, Boets B, Steyaert J

Abstract
Autism spectrum disorders (ASD) have a high degree of heritability, but there is still much debate about specific causal genes and pathways. To gain insight into patterns of transmission, research has focused on the relatedness of quantitative autism traits (QAT) between family members, mostly using questionnaires. Yet, different kinds of bias may influence research results. In this paper, we focus on possible informant effects and, taking these into account, on possible intergenerational transmission of QAT. This study used multiple informant data retrieved via the Social Responsiveness Scale from 170 families with at least one member with ASD. Using intraclass correlations (ICCs) and mixed model analyses, we investigated inter-informant agreement and differences between parent and teacher reports on children and between self- and other-reports on adults. Using structural equation modelling (SEM), we investigated the relatedness of QAT between family members in ASD families. Parent-teacher agreement about social responsiveness was poor, especially for children with ASD, though agreement between parents was moderate to strong for affected and unaffected children. Agreement between self- and other-report in adult men was good, but only moderate in women. Agreement did not differ between adults with and without ASD. While accounting for informant effects, our SEM results corroborated the assortative mating theory and the intergenerational transmission of QAT from both fathers and mothers to their offspring.

PMID: 25086652 [PubMed - indexed for MEDLINE]

In Tribute to Bob Blanchard: Divergent Behavioral Phenotypes of 16p11.2 Deletion Mice Reared in Same-Genotype Versus Mixed-Genotype Cages.

June 13, 2015 - 7:13am

In Tribute to Bob Blanchard: Divergent Behavioral Phenotypes of 16p11.2 Deletion Mice Reared in Same-Genotype Versus Mixed-Genotype Cages.

Physiol Behav. 2015 Apr 15;

Authors: Yang M, Lewis F, Foley G, Crawley JN

Abstract
Mouse models offer indispensable heuristic tools for studying genetic and environmental causes of neuropsychiatric disorders, including autism. Development of useful animal models of complex human behaviors depends not only on extensive knowledge of the human disease, but also on a deep understanding of animal behavior and ethology. Robert and Caroline Blanchard pioneered a number of elegant social paradigms in rodents. Their early work led to systematic delineations of rodent naturalist defensive behaviors, which were proven to be highly useful models of human psychiatric disorders, including fear and anxiety. Their work using the Visible Burrow System to study social stress in rats represented an unprecedented approach to study biological mechanisms of depression. In recent years, their extensive knowledge of mouse behavior and ethology enabled them to quickly become leading figures in the field of behavioral genetics of autism. To commemorate Robert Blanchard's influences on animal models of human psychiatric disorders, here we describe a study conceptualized and led by Mu Yang who was trained as a graduate student in the Blanchard laboratory in the early 2000s. This investigation focuses on social housing in a genetic mouse model of 16p11.2 deletion syndrome. Heterozygous deletions and duplications of a segment containing about 29 genes on human chromosome 16 appear in approximately 0.5-1% of all cases of autism. 16p11.2 deletion syndrome is also associated with intellectual disabilities and speech impairments. Our previous studies showed that a mouse model of 16p11.2 deletion syndrome exhibited deficits in vocalizations and novel object recognition, as compared to wildtype littermate control cagemates. In the spirit of Bob Blanchard's careful attention to the role of social dominance in rodent behaviors, we became interested in the question of whether behavioral outcomes of a mutation differ when mutants are housed in mixed genotype cages, versus housing only mutants together in one group cage, and only wildtype littermates together in another group cage after weaning. 16p11.2 deletion presented a particularly good model organism to investigate this question, because the heterozygotes are smaller than their wildtype littermates, and may therefore become subordinate to their larger cagemates. Wild type and heterozygotes were housed with cagemates of the same genotype (same-genotype cage) or with cagemates of the opposite genotype (mixed-genotype cage). Current results replicated social vocalization and object recognition deficits that we previously found in heterozygotes lived in mixed-genotype cages. In contrast, heterozygotes that lived in same-genotype cages emitted normal numbers of vocalizations during male-female interactions, and displayed normal novel object recognition, indicating that the deletion per se was not sufficient to cause cognitive or social deficits. Social approach, same-sex social interaction, anxiety-related behavior, depression-related behavior, and open field exploration were not different between genotypes, and were not affected by housing in mixed versus in same-genotype cages. These findings suggest that elements of the home cage social environment could interact with genotype to impact aspects of disease phenotypes. Current findings are discussed as potentially reflecting behavioral deficits resulted from social stress, as inspired by a seminal paper by Bob and Caroline Blanchard [1].

PMID: 26066718 [PubMed - as supplied by publisher]

Parents' Perceptions of the Usefulness of Chromosomal Microarray Analysis for Children with Autism Spectrum Disorders.

June 13, 2015 - 7:13am

Parents' Perceptions of the Usefulness of Chromosomal Microarray Analysis for Children with Autism Spectrum Disorders.

J Autism Dev Disord. 2015 Jun 12;

Authors: Reiff M, Giarelli E, Bernhardt BA, Easley E, Spinner NB, Sankar PL, Mulchandani S

Abstract
Clinical guidelines recommend chromosomal microarray analysis (CMA) for all children with autism spectrum disorders (ASDs). We explored the test's perceived usefulness among parents of children with ASD who had undergone CMA, and received a result categorized as pathogenic, variant of uncertain significance, or negative. Fifty-seven parents participated in a semi-structured telephone interview, and 50 also completed a survey. Most parents reported that CMA was helpful for their child and family. Major themes regarding perceived usefulness were: medical care, educational and behavioral interventions, causal explanation, information for family members, and advancing knowledge. Limits to utility, uncertainties and negative outcomes were also identified. Our findings highlight the importance of considering both health and non-health related utility in genomic testing.

PMID: 26066358 [PubMed - as supplied by publisher]

PWS/AS MS-MLPA Confirms Maternal Origin of 15q11.2 Microduplication.

June 13, 2015 - 7:13am
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PWS/AS MS-MLPA Confirms Maternal Origin of 15q11.2 Microduplication.

Case Rep Genet. 2015;2015:474097

Authors: Dawson AJ, Cox J, Hovanes K, Spriggs E

Abstract
The proximal region of the long arm of chromosome 15q11.2-q13 is associated with various neurodevelopmental disorders, including Prader-Willi (PWS) and Angelman (AS) syndromes, autism, and other developmental abnormalities resulting from deletions and duplications. In addition, this region encompasses imprinted genes that cause PWS or AS, depending on the parent-of-origin. This imprinting allows for diagnosis of PWS or AS based on methylation status using methylation sensitive (MS) multiplex ligation dependent probe amplification (MLPA). Maternally derived microduplications at 15q11.2-q13 have been associated with autism and other neuropsychiatric disorders. Multiple methods have been used to determine the parent-of-origin for 15q11.2-q13 microdeletions and microduplications. In the present study, a four-year-old nondysmorphic female patient with developmental delay was found to have a de novo ~5 Mb duplication within 15q11.2 by oligonucleotide genomic array. In order to determine the significance of this microduplication to the clinical phenotype, the parent-of-origin needed to be identified. The PWS/AS MS-MLPA assay is generally used to distinguish between deletion and uniparental disomy (UPD) of 15q11.2-q13, resulting in either PWS or AS. However, our study shows that PWS/AS MS-MLPA can also efficiently distinguish the parental origin of duplications of 15q11.2-q13.

PMID: 26064710 [PubMed]

Differential gene expression patterns in developing sexually dimorphic rat brain regions exposed to antiandrogenic, estrogenic, or complex endocrine disruptor mixtures: glutamatergic synapses as target.

June 13, 2015 - 7:13am
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Differential gene expression patterns in developing sexually dimorphic rat brain regions exposed to antiandrogenic, estrogenic, or complex endocrine disruptor mixtures: glutamatergic synapses as target.

Endocrinology. 2015 Apr;156(4):1477-93

Authors: Lichtensteiger W, Bassetti-Gaille C, Faass O, Axelstad M, Boberg J, Christiansen S, Rehrauer H, Georgijevic JK, Hass U, Kortenkamp A, Schlumpf M

Abstract
The study addressed the question whether gene expression patterns induced by different mixtures of endocrine disrupting chemicals (EDCs) administered in a higher dose range, corresponding to 450×, 200×, and 100× high-end human exposure levels, could be characterized in developing brain with respect to endocrine activity of mixture components, and which developmental processes were preferentially targeted. Three EDC mixtures, A-Mix (anti-androgenic mixture) with 8 antiandrogenic chemicals (di-n-butylphthalate, diethylhexylphthalate, vinclozolin, prochloraz, procymidone, linuron, epoxiconazole, and DDE), E-Mix (estrogenic mixture) with 4 estrogenic chemicals (bisphenol A, 4-methylbenzylidene camphor, 2-ethylhexyl 4-methoxycinnamate, and butylparaben), a complex mixture, AEP-Mix, containing the components of A-Mix and E-Mix plus paracetamol, and paracetamol alone, were administered by oral gavage to rat dams from gestation day 7 until weaning. General developmental endpoints were not affected by EDC mixtures or paracetamol. Gene expression was analyzed on postnatal day 6, during sexual brain differentiation, by exon microarray in medial preoptic area in the high-dose group, and by real-time RT-PCR in medial preoptic area and ventromedial hypothalamus in all dose groups. Expression patterns were mixture, sex, and region specific. Effects of the analgesic drug paracetamol, which exhibits antiandrogenic activity in peripheral systems, differed from those of A-Mix. All mixtures had a strong, mixture-specific impact on genes encoding for components of excitatory glutamatergic synapses and genes controlling migration and pathfinding of glutamatergic and GABAergic neurons, as well as genes linked with increased risk of autism spectrum disorders. Because development of glutamatergic synapses is regulated by sex steroids also in hippocampus, this may represent a general target of ECD mixtures.

PMID: 25607892 [PubMed - indexed for MEDLINE]

Maternal pre-pregnancy weight and externalising behaviour problems in preschool children: a UK-based twin study.

June 13, 2015 - 7:13am
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Maternal pre-pregnancy weight and externalising behaviour problems in preschool children: a UK-based twin study.

BMJ Open. 2014;4(10):e005974

Authors: Antoniou EE, Fowler T, Reed K, Southwood TR, McCleery JP, Zeegers MP

Abstract
OBJECTIVE: To estimate the heritability of child behaviour problems and investigate the association between maternal pre-pregnancy overweight and child behaviour problems in a genetically sensitive design.
DESIGN: Observational cross-sectional study.
SETTING: The Twins and Multiple Births Association Heritability Study (TAMBAHS) is an online UK-wide volunteer-based study investigating the development of twins from birth until 5 years of age.
PARTICIPANTS: A total of 443 (16% of the initial registered members) mothers answered questions on pre-pregnancy weight and their twins' internalising and externalising problems using the Child Behavior Checklist and correcting for important covariates including gestational age, twins' birth weight, age and sex, mother's educational level and smoking (before, during and after pregnancy).
PRIMARY OUTCOMES: The heritability of behaviour problems and their association with maternal pre-pregnancy weight.
RESULTS: The genetic analysis suggested that genetic and common environmental factors account for most of the variation in externalising disorders (an ACE model was the most parsimonious with genetic factors (A) explaining 46% (95% CI 33% to 60%) of the variance, common environment (C) explaining 42% (95% CI 27% to 54%) and non-shared environmental factors (E) explaining 13% (95% CI 10% to 16%) of the variance. For internalising problems, a CE model was the most parsimonious model with the common environment explaining 51% (95% CI 44% to 58%) of the variance and non-shared environment explaining 49% (95% CI 42% to 56%) of the variance. Moreover, the regression analysis results suggested that children of overweight mothers showed a trend (OR=1.10, 95% CI 0.58% to 2.06) towards being more aggressive and exhibit externalising behaviours compared to children of normal weight mothers.
CONCLUSIONS: Maternal pre-pregnancy weight may play a role in children's aggressive behaviour.

PMID: 25314961 [PubMed - indexed for MEDLINE]

Quantitative phosphoproteomics of murine Fmr1-KO cell lines provides new insights into FMRP-dependent signal transduction mechanisms.

June 13, 2015 - 7:13am
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Quantitative phosphoproteomics of murine Fmr1-KO cell lines provides new insights into FMRP-dependent signal transduction mechanisms.

J Proteome Res. 2014 Oct 3;13(10):4388-97

Authors: Matic K, Eninger T, Bardoni B, Davidovic L, Macek B

Abstract
Fragile X mental retardation protein (FMRP) is an RNA-binding protein that has a major effect on neuronal protein synthesis. Transcriptional silencing of the FMR1 gene leads to loss of FMRP and development of Fragile X syndrome (FXS), the most common known hereditary cause of intellectual impairment and autism. Here we utilize SILAC-based quantitative phosphoproteomics to analyze murine FMR1(-) and FMR1(+) fibroblastic cell lines derived from FMR1-KO embryos to identify proteins and phosphorylation sites dysregulated as a consequence of FMRP loss. We quantify FMRP-related changes in the levels of 5,023 proteins and 6,133 phosphorylation events and map them onto major signal transduction pathways. Our study confirms global downregulation of the MAPK/ERK pathway and decrease in phosphorylation level of ERK1/2 in the absence of FMRP, which is connected to attenuation of long-term potentiation. We detect differential expression of several key proteins from the p53 pathway, pointing to the involvement of p53 signaling in dysregulated cell cycle control in FXS. Finally, we detect differential expression and phosphorylation of proteins involved in pre-mRNA processing and nuclear transport, as well as Wnt and calcium signaling, such as PLC, PKC, NFAT, and cPLA2. We postulate that calcium homeostasis is likely affected in molecular pathogenesis of FXS.

PMID: 25168779 [PubMed - indexed for MEDLINE]

N-myristoylation regulates the axonal distribution of the Fragile X-related protein FXR2P.

June 13, 2015 - 7:13am
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N-myristoylation regulates the axonal distribution of the Fragile X-related protein FXR2P.

Mol Cell Neurosci. 2014 Sep;62:42-50

Authors: Stackpole EE, Akins MR, Fallon JR

Abstract
Fragile X syndrome, the leading cause of inherited intellectual disability and autism, is caused by loss of function of Fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein that regulates local protein synthesis in the somatodendritic compartment. However, emerging evidence also indicates important roles for FMRP in axonal and presynaptic functions. In particular, FMRP and its homologue FXR2P localize axonally and presynaptically to discrete endogenous structures in the brain termed Fragile X granules (FXGs). FXR2P is a component of all FXGs and is necessary for the axonal and presynaptic localization of FMRP to these structures. We therefore sought to identify and characterize structural features of FXR2P that regulate its axonal localization. Sequence analysis reveals that FXR2P harbors a consensus N-terminal myristoylation sequence (MGXXXS) that is absent in FMRP. Using click chemistry with wild type and an unmyristoylatable G2A mutant we demonstrate that FXR2P is N-myristoylated on glycine 2, establishing it as a lipid-modified RNA binding protein. To investigate the role of FXR2P N-myristoylation in neurons we generated fluorescently tagged wild type and unmyristoylatable FXR2P (WT and G2A, respectively) and expressed them in primary cortical cultures. Both FXR2P(WT) and FXR2P(G2A) are expressed at equivalent overall levels and are capable of forming FMRP-containing axonal granules. However, FXR2P(WT) granules are largely restricted to proximal axonal segments while granules formed with unmyristoylatable FXR2P(G2A) are localized throughout the axonal arbor, including in growth cones. These studies indicate that N-terminal myristoylation of the RNA binding protein FXR2P regulates its localization within the axonal arbor. Moreover, since FMRP localization within axonal domains requires its association with FXR2P, these findings suggest that FXR2P lipid modification is a control point for the axonal and presynaptic distribution of FMRP.

PMID: 25109237 [PubMed - indexed for MEDLINE]

Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment.

June 13, 2015 - 7:13am
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Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment.

Eur J Hum Genet. 2014 Oct;22(10):1165-71

Authors: Ceroni F, Simpson NH, Francks C, Baird G, Conti-Ramsden G, Clark A, Bolton PF, Hennessy ER, Donnelly P, Bentley DR, Martin H, IMGSAC, SLI Consortium, WGS500 Consortium, Parr J, Pagnamenta AT, Maestrini E, Bacchelli E, Fisher SE, Newbury DF

Abstract
Specific language impairment (SLI), an unexpected failure to develop appropriate language skills despite adequate non-verbal intelligence, is a heterogeneous multifactorial disorder with a complex genetic basis. We identified a homozygous microdeletion of 21,379 bp in the ZNF277 gene (NM_021994.2), encompassing exon 5, in an individual with severe receptive and expressive language impairment. The microdeletion was not found in the proband's affected sister or her brother who had mild language impairment. However, it was inherited from both parents, each of whom carries a heterozygous microdeletion and has a history of language problems. The microdeletion falls within the AUTS1 locus, a region linked to autistic spectrum disorders (ASDs). Moreover, ZNF277 is adjacent to the DOCK4 and IMMP2L genes, which have been implicated in ASD. We screened for the presence of ZNF277 microdeletions in cohorts of children with SLI or ASD and panels of control subjects. ZNF277 microdeletions were at an increased allelic frequency in SLI probands (1.1%) compared with both ASD family members (0.3%) and independent controls (0.4%). We performed quantitative RT-PCR analyses of the expression of IMMP2L, DOCK4 and ZNF277 in individuals carrying either an IMMP2L_DOCK4 microdeletion or a ZNF277 microdeletion. Although ZNF277 microdeletions reduce the expression of ZNF277, they do not alter the levels of DOCK4 or IMMP2L transcripts. Conversely, IMMP2L_DOCK4 microdeletions do not affect the expression levels of ZNF277. We postulate that ZNF277 microdeletions may contribute to the risk of language impairments in a manner that is independent of the autism risk loci previously described in this region.

PMID: 24518835 [PubMed - indexed for MEDLINE]

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