pubmed: autism and genetics

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Zylka et al. reply.

September 30, 2014 - 7:56am
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Zylka et al. reply.

Nature. 2014 Aug 7;512(7512):E2

Authors: Zylka MJ, Philpot BD, King IF

PMID: 25100485 [PubMed - indexed for MEDLINE]

Epilepsy and outcome in FOXG1-related disorders.

September 30, 2014 - 7:56am
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Epilepsy and outcome in FOXG1-related disorders.

Epilepsia. 2014 Aug;55(8):1292-300

Authors: Seltzer LE, Ma M, Ahmed S, Bertrand M, Dobyns WB, Wheless J, Paciorkowski AR

Abstract
OBJECTIVE: FOXG1-related disorders are associated with severe intellectual disability, absent speech with autistic features, and epilepsy. Children with deletions or intragenic mutations of FOXG1 also have postnatal microcephaly, morphologic abnormalities of the corpus callosum, and choreiform movements. Duplications of 14q12 often present with infantile spasms, and have subsequent intellectual disability with autistic features. Long-term epilepsy outcome and response to treatment have not been studied systematically in a well-described cohort of subjects with FOXG1-related disorders. We report on the epilepsy features and developmental outcome of 23 new subjects with deletions or intragenic mutations of FOXG1, and 7 subjects with duplications.
METHODS: Subjects had either chromosomal microarray or FOXG1 gene sequencing performed as part of routine clinical care. Development and epilepsy follow-up data were collected from medical records from treating neurologists and through telephone parental interviews using standardized questionnaires.
RESULTS: Epilepsy was diagnosed in 87% of the subjects with FOXG1-related disorders. The mean age of epilepsy diagnosis in FOXG1 duplications was significantly younger than those with deletions/intragenic mutations (p = 0.0002). All of the duplication FOXG1 children with infantile spasms responded to hormonal therapy, and only one required long-term antiepileptic therapy. In contrast, more children with deletions/intragenic mutations required antiepileptic drugs on follow-up (p < 0.0005). All subjects with FOXG1-related disorders had neurodevelopmental disabilities after 3 years of age, regardless of the epilepsy type or intractability of seizures. All had impaired verbal language and social contact, and three duplication subjects were formally diagnosed with autism. Subjects with deletion/intragenic mutations, however, had significantly worse ambulation (p = 0.04) and functional hand use (p < 0.0005).
SIGNIFICANCE: Epilepsy and developmental outcome characteristics allow clinicians to distinguish among the FOXG1-related disorders. Further genotype-phenotype studies of FOXG1 may help to elucidate why children develop different forms of developmental epilepsy.

PMID: 24836831 [PubMed - indexed for MEDLINE]

Identification and glycerol-induced correction of misfolding mutations in the X-linked mental retardation gene CASK.

September 30, 2014 - 7:56am
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Identification and glycerol-induced correction of misfolding mutations in the X-linked mental retardation gene CASK.

PLoS One. 2014;9(2):e88276

Authors: LaConte LE, Chavan V, Mukherjee K

Abstract
The overwhelming amount of available genomic sequence variation information demands a streamlined approach to examine known pathogenic mutations of any given protein. Here we seek to outline a strategy to easily classify pathogenic missense mutations that cause protein misfolding and are thus good candidates for chaperone-based therapeutic strategies, using previously identified mutations in the gene CASK. We applied a battery of bioinformatics algorithms designed to predict potential impact on protein structure to five pathogenic missense mutations in the protein CASK that have been shown to underlie pathologies ranging from X-linked mental retardation to autism spectrum disorder. A successful classification of the mutations as damaging was not consistently achieved despite the known pathogenicity. In addition to the bioinformatics analyses, we performed molecular modeling and phylogenetic comparisons. Finally, we developed a simple high-throughput imaging assay to measure the misfolding propensity of the CASK mutants in situ. Our data suggests that a phylogenetic analysis may be a robust method for predicting structurally damaging mutations in CASK. Mutations in two evolutionarily invariant residues (Y728C and W919R) exhibited a strong propensity to misfold and form visible aggregates in the cytosolic milieu. The remaining mutations (R28L, Y268H, and P396S) showed no evidence of aggregation and maintained their interactions with known CASK binding partners liprin-α3 Mint-1, and Veli, indicating an intact structure. Intriguingly, the protein aggregation caused by the Y728C and W919R mutations was reversed by treating the cells with a chemical chaperone (glycerol), providing a possible therapeutic strategy for treating structural mutations in CASK in the future.

PMID: 24505460 [PubMed - indexed for MEDLINE]

Neural measures of social attention across the first years of life: characterizing typical development and markers of autism risk.

September 30, 2014 - 7:56am
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Neural measures of social attention across the first years of life: characterizing typical development and markers of autism risk.

Dev Cogn Neurosci. 2014 Apr;8:131-43

Authors: Luyster RJ, Powell C, Tager-Flusberg H, Nelson CA

Abstract
Few studies employing event-related potentials (ERPs) to examine infant perception/cognition have systematically characterized age-related changes over the first few years of life. Establishing a 'normative' template of development is important in its own right, and doing so may also better highlight points of divergence for high-risk populations of infants, such as those at elevated genetic risk for autism spectrum disorder (ASD). The present investigation explores the developmental progression of the P1, N290, P400 and Nc components for a large sample of young children between 6 and 36 months of age, addressing age-related changes in amplitude, sensitivity to familiar and unfamiliar stimuli and hemispheric lateralization. Two samples of infants are included: those at low- and high-risk for ASD. The four components of interest show differential patterns of change over time and hemispheric lateralization; however, infants at low- and high-risk for ASD do not show significant differences in patterns of neural response to faces. These results will provide a useful point of reference for future developmental cognitive neuroscience research targeting both typical development and vulnerable populations.

PMID: 24183618 [PubMed - indexed for MEDLINE]

MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons.

September 30, 2014 - 7:56am
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MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons.

PLoS One. 2013;8(6):e65069

Authors: Larimore J, Ryder PV, Kim KY, Ambrose LA, Chapleau C, Calfa G, Gross C, Bassell GJ, Pozzo-Miller L, Smith Y, Talbot K, Park IH, Faundez V

Abstract
Clinical, epidemiological, and genetic evidence suggest overlapping pathogenic mechanisms between autism spectrum disorder (ASD) and schizophrenia. We tested this hypothesis by asking if mutations in the ASD gene MECP2 which cause Rett syndrome affect the expression of genes encoding the schizophrenia risk factor dysbindin, a subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), and associated interacting proteins. We measured mRNA and protein levels of key components of a dysbindin interaction network by, quantitative real time PCR and quantitative immunohistochemistry in hippocampal samples of wild-type and Mecp2 mutant mice. In addition, we confirmed results by performing immunohistochemistry of normal human hippocampus and quantitative qRT-PCR of human inducible pluripotent stem cells (iPSCs)-derived human neurons from Rett syndrome patients. We defined the distribution of the BLOC-1 subunit pallidin in human and mouse hippocampus and contrasted this distribution with that of symptomatic Mecp2 mutant mice. Neurons from mutant mice and Rett syndrome patients displayed selectively reduced levels of pallidin transcript. Pallidin immunoreactivity decreased in the hippocampus of symptomatic Mecp2 mutant mice, a feature most prominent at asymmetric synapses as determined by immunoelectron microcopy. Pallidin immunoreactivity decreased concomitantly with reduced BDNF content in the hippocampus of Mecp2 mice. Similarly, BDNF content was reduced in the hippocampus of BLOC-1 deficient mice suggesting that genetic defects in BLOC-1 are upstream of the BDNF phenotype in Mecp2 deficient mice. Our results demonstrate that the ASD-related gene Mecp2 regulates the expression of components belonging to the dysbindin interactome and these molecular differences may contribute to synaptic phenotypes that characterize Mecp2 deficiencies and ASD.

PMID: 23750231 [PubMed - indexed for MEDLINE]

SLC6A4 markers modulate platelet 5-HT level and specific behaviors of autism: A study from an Indian population.

September 28, 2014 - 7:20am

SLC6A4 markers modulate platelet 5-HT level and specific behaviors of autism: A study from an Indian population.

Prog Neuropsychopharmacol Biol Psychiatry. 2014 Sep 24;

Authors: Jaiswal P, Guhathakurta S, Singh AS, Verma D, Pandey M, Varghese M, Sinha S, Ghosh S, Mohanakumar KP, Rajamma U

Abstract
Presence of platelet hyperserotonemia and effective amelioration of behavioral dysfunctions by selective serotonin reuptake inhibitors (SSRI) in autism spectrum disorders (ASD) indicate that irregularities in serotonin (5-HT) reuptake and its homeostasis could be the basis of behavioral impairments in ASD patients. SLC6A4, the gene encoding serotonin transporter (SERT) is considered as a potential susceptibility gene for ASD, since it is a quantitative trait locus for blood 5-HT levels. Three functional polymorphisms, 5-HTTLPR, STin2 and 3'UTR-SNP of SLC6A4 are extensively studied for possible association with the disorder, with inconclusive outcome. In the present study, we investigated association of these polymorphisms with platelet 5-HT content and symptoms severity as revealed by childhood autism rating scale in ASD children from an Indian population. Higher 5-HT level observed in ASD was highly significant in children with heterozygous and homozygous genotypes comprising of minor alleles of the markers. Quantitative transmission disequilibrium test demonstrated significant genetic effect of STin2 allele as well as STin2/3'UTR-SNP and 5-HTTLPR/3'UTR-SNP haplotypes on 5-HT levels, but no direct association with overall CARS score and ASD phenotype. Significant genetic effect of the markers on specific behavioral phenotypes was observed for various sub-phenotypes of CARS in quantitative trait analysis. Even though the 5-HT level was not associated with severity of behavioral CARS score, a significant negative relationship was observed for 5-HT levels and level and consistency of intellectual response and general impression in ASD children. Population-based study revealed higher distribution of the haplotype 10/G of STin2/3'-UTR in male controls, suggesting protective effect of this haplotype in male cases. Overall results of the study suggest that SLC6A4 markers have specific genetic effect on individual ASD behavioral attributes, might be through the modulation of 5-HT content.

PMID: 25261775 [PubMed - as supplied by publisher]

SnapShot: FMRP Interacting Proteins.

September 27, 2014 - 7:03am

SnapShot: FMRP Interacting Proteins.

Cell. 2014 Sep 25;159(1):218-218.e1

Authors: Pasciuto E, Bagni C

Abstract
The Fragile X syndrome, caused by the absence or mutation of fragile X mental retardation protein, FMRP, is a the common component of inherited intellectual disability and autism. This SnapShot surveys the protein interaction partners of FMRP, focusing on the cellular pathways in which they are involved.

PMID: 25259928 [PubMed - as supplied by publisher]

A complex Xp11.22 deletion in a patient with syndromic autism: Exploration of FAM120C as a positional candidate gene for autism.

September 27, 2014 - 7:03am

A complex Xp11.22 deletion in a patient with syndromic autism: Exploration of FAM120C as a positional candidate gene for autism.

Am J Med Genet A. 2014 Sep 24;

Authors: De Wolf V, Crepel A, Schuit F, van Lommel L, Ceulemans B, Steyaert J, Seuntjens E, Peeters H, Devriendt K

Abstract
We present a male patient with sporadic Aarskog syndrome, cleft palate, mild intellectual disability, and autism spectrum disorder (ASD). A submicroscopic discontiguous deletion was detected on chromosome Xp11.2 encompassing FGD1, FAM120C, and PHF8. That the deletion encompassed FGD1 (exons 2-8) explains the Aarskog features while the deletion of PHF8 most likely explains the cleft palate and mild intellectual disability. We identify FAM120C as a novel X-linked candidate gene for autism for two reasons: first, a larger deletion encompassing FAM120C segregates with autism in a previously reported family and second, there is recent evidence that FAM120C interacts with CYFIP1, part of the FMRP (Fragile X Mental Retardation Protein) network. In the current study, resequencing of FAM120C in 87 Belgian male patients with autism spectrum disorder identified no novel mutations. Expression of Fam120c in mouse tissues showed enriched expression in pituitary, cerebellum, cortex, and pancreatic islets of Langerhans. Additionally, we found a cortical expression pattern of Fam120c similar to that of Fmr1. In conclusion, FAM120C is a novel candidate gene for autism spectrum disorder based on genetic evidence and the brain expression pattern. Thereby we highlight a role for FMRP network genes in ASD. © 2014 Wiley Periodicals, Inc.

PMID: 25258334 [PubMed - as supplied by publisher]

ADHD bör uppmärksammas mer - tidiga insatser spar lidande.

September 26, 2014 - 6:41am

ADHD bör uppmärksammas mer - tidiga insatser spar lidande.

Lakartidningen. 2014;111

Authors: Fernell E, Nylander L, Kadesjö B, Gillberg C

Abstract
ADHD is a common neurodevelopmental/neuropsychiatric disorder affecting about 5 percent of children. About 2-3 percent meet diagnostic criteria in adulthood as well. The core symptoms include inattention with or without hyperactivity/restlessness and impulsivity. The main cognitive deficit involves executive functions, probably related to a weak reward system. Symptoms will affect daily functioning at home, among friends and at school/work. In girls and women particularly, a correct diagnosis of ADHD is often late, or is not at all appropriately considered. Co-existing disorders are common; dyslexia, developmental coordination disorder, emotional lability, conduct disorder, autistic symptoms, obsessive compulsive disorder, depression, bipolar disorder, Tourette syndrome, eating disorder, sleeping disorder, and substance abuse. Extensive research in ADHD has increased knowledge in genetics, neurobiology, neuropsychology, intervention, and treatment. Despite this, many individuals with ADHD are not offered a correct assessment, and accordingly, not given appropriate support and treatment.

PMID: 25253607 [PubMed - as supplied by publisher]

[Genetics applied to clinical practice in neurodevelopmental disorders.]

September 26, 2014 - 6:41am

[Genetics applied to clinical practice in neurodevelopmental disorders.]

Rev Neurol. 2014 Feb 24;58(S01):S65-S70

Authors: Fernandez-Jaen A, Cigudosa JC, Martin Fernandez-Mayoralas D, Suela-Rubio J, Fernandez-Perrone AL, Calleja-Perez B, Lopez-Martin S

Abstract
The medical literature contains a wide body of evidence supporting genetic involvement in neurodevelopmental disorders. Advances made in genetics and technology have increased the diagnostic cost-effectiveness of current studies from 3-5% to 30-40% in patients with intellectual disability or autism spectrum disorders. In this regard, chromosomal microarray studies display greater diagnostic power than conventional techniques (karyotype, subtelomeric analyses, etc.). The latest protocols in the biomedical field of the genetic study of these disorders cite chromosomal microarrays as the first-line analysis, while also recommending other specific studies depending on the patient's clinical features (fragile X syndrome, PTEN mutation, etc.). In the evaluation of other neurodevelopmental disorders (attention deficit hyperactivity disorder, learning disorders, etc.), the number of genetic tests carried out is limited and conditioned by the clinical characteristics or the patient's familial or personal history. Even in these situations, there are no genetic referral or evaluation protocols.

PMID: 25252670 [PubMed - as supplied by publisher]

[Synapse maturation and autism: learning from neuroligin model mice].

September 26, 2014 - 6:41am
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[Synapse maturation and autism: learning from neuroligin model mice].

Nihon Shinkei Seishin Yakurigaku Zasshi. 2014 Feb;34(1):1-4

Authors: Tabuchi K, Hang W, Asgar NF, Pramanik G

Abstract
Autism is a neurodevelopmental disorder characterized by impairments in social interaction, communication, and restricted and repetitive behavior. Synaptic defects have been implicated in autism; nevertheless, the cause is still largely unknown. A mutation that substitutes cysteine for arginine at residue 451 of Neuroligin-3 (R451C) is the first monogenic mutation identified in idiopathic autism patients. To study the relationship between this mutation and autism, we generated knock-in mice that recapitulated this mutation. The knock-in mice were born and grew up normally without showing any major physical phenotypes, but showed a deficit in social interaction. We studied synaptic function in the layer II/III pyramidal neurons in the somatosensory cortex and found inhibitory synaptic transmission was enhanced in the knock-in mice. The administration of GABA blocker rescued social interaction, suggesting that this caused autistic behavior in these mice. We also found, by Morris water maze test, that spatial learning and memory were significantly enhanced in the knock-in mice. Electrophysiology in the CA1 region of the hippocampus revealed that LTP, the NMDA/AMPA ratio, and NR2B function were enhanced, indicating that synaptic maturation was impaired in the knock-in mice. This may cause the deficit in social behavior and extraordinary memory ability occasionally seen in autistic patients.

PMID: 25069265 [PubMed - indexed for MEDLINE]

iPSC-derived neurons as a higher-throughput readout for autism: promises and pitfalls.

September 26, 2014 - 6:41am
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iPSC-derived neurons as a higher-throughput readout for autism: promises and pitfalls.

Trends Mol Med. 2014 Feb;20(2):91-104

Authors: Prilutsky D, Palmer NP, Smedemark-Margulies N, Schlaeger TM, Margulies DM, Kohane IS

Abstract
The elucidation of disease etiologies and establishment of robust, scalable, high-throughput screening assays for autism spectrum disorders (ASDs) have been impeded by both inaccessibility of disease-relevant neuronal tissue and the genetic heterogeneity of the disorder. Neuronal cells derived from induced pluripotent stem cells (iPSCs) from autism patients may circumvent these obstacles and serve as relevant cell models. To date, derived cells are characterized and screened by assessing their neuronal phenotypes. These characterizations are often etiology-specific or lack reproducibility and stability. In this review, we present an overview of efforts to study iPSC-derived neurons as a model for autism, and we explore the plausibility of gene expression profiling as a reproducible and stable disease marker.

PMID: 24374161 [PubMed - indexed for MEDLINE]

Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis.

September 26, 2014 - 6:41am
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Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis.

Genes Brain Behav. 2014 Jan;13(1):69-86

Authors: Stilling RM, Dinan TG, Cryan JF

Abstract
To date, there is rapidly increasing evidence for host-microbe interaction at virtually all levels of complexity, ranging from direct cell-to-cell communication to extensive systemic signalling, and involving various organs and organ systems, including the central nervous system. As such, the discovery that differential microbial composition is associated with alterations in behaviour and cognition has significantly contributed to establishing the microbiota-gut-brain axis as an extension of the well-accepted gut-brain axis concept. Many efforts have been focused on delineating a role for this axis in health and disease, ranging from stress-related disorders such as depression, anxiety and irritable bowel syndrome to neurodevelopmental disorders such as autism. There is also a growing appreciation of the role of epigenetic mechanisms in shaping brain and behaviour. However, the role of epigenetics in informing host-microbe interactions has received little attention to date. This is despite the fact that there are many plausible routes of interaction between epigenetic mechanisms and the host-microbiota dialogue. From this new perspective we put forward novel, yet testable, hypotheses. Firstly, we suggest that gut-microbial products can affect chromatin plasticity within their host's brain that in turn leads to changes in neuronal transcription and eventually alters host behaviour. Secondly, we argue that the microbiota is an important mediator of gene-environment interactions. Finally, we reason that the microbiota itself may be viewed as an epigenetic entity. In conclusion, the fields of (neuro)epigenetics and microbiology are converging at many levels and more interdisciplinary studies are necessary to unravel the full range of this interaction.

PMID: 24286462 [PubMed - indexed for MEDLINE]

Variants in the 1q21 risk region are associated with a visual endophenotype of autism and schizophrenia.

September 26, 2014 - 6:41am
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Variants in the 1q21 risk region are associated with a visual endophenotype of autism and schizophrenia.

Genes Brain Behav. 2014 Feb;13(2):144-51

Authors: Goodbourn PT, Bosten JM, Bargary G, Hogg RE, Lawrance-Owen AJ, Mollon JD

Abstract
Deficits in sensitivity to visual stimuli of low spatial frequency and high temporal frequency (so-called frequency-doubled gratings) have been demonstrated both in schizophrenia and in autism spectrum disorder (ASD). Such basic perceptual functions are ideal candidates for molecular genetic study, because the underlying neural mechanisms are well characterized; but they have sometimes been overlooked in favor of cognitive and neurophysiological endophenotypes, for which neural substrates are often unknown. Here, we report a genome-wide association study of a basic visual endophenotype associated with psychological disorder. Sensitivity to frequency-doubled gratings was measured in 1060 healthy young adults, and analyzed for association with genotype using linear regression at 642 758 single nucleotide polymorphism (SNP) markers. A significant association (P = 7.9 × 10(-9) ) was found with the SNP marker rs1797052, situated in the 5'-untranslated region of PDZK1; each additional copy of the minor allele was associated with an increase in sensitivity equivalent to more than half a standard deviation. A permutation procedure, which accounts for multiple testing, showed that the association was significant at the α = 0.005 level. The region on chromosome 1q21.1 surrounding PDZK1 is an established susceptibility locus both for schizophrenia and for ASD, mirroring the common association of the visual endophenotype with the two disorders. PDZK1 interacts with N-methyl-d-aspartate receptors and neuroligins, which have been implicated in the etiologies of schizophrenia and ASD. These findings suggest that perceptual abnormalities observed in two different disorders may be linked by common genetic elements.

PMID: 24152035 [PubMed - indexed for MEDLINE]

Maternal Intake of Supplemental Iron and Risk of Autism Spectrum Disorder.

September 25, 2014 - 6:26am

Maternal Intake of Supplemental Iron and Risk of Autism Spectrum Disorder.

Am J Epidemiol. 2014 Sep 22;

Authors: Schmidt RJ, Tancredi DJ, Krakowiak P, Hansen RL, Ozonoff S

Abstract
Iron deficiency affects 40%-50% of pregnancies. Iron is critical for early neurodevelopmental processes that are dysregulated in autism spectrum disorder (ASD). We examined maternal iron intake in relation to ASD risk in California-born children enrolled in a population-based case-control study (the Childhood Autism Risks from Genetics and the Environment (CHARGE) Study) from 2003 to 2009 with a diagnosis of ASD (n = 520) or typical development (n = 346) that was clinically confirmed using standardized assessments. Mean maternal daily iron intake was quantified on the basis of frequency, dose, and brands of supplements and cereals consumed each month from 3 months before pregnancy through the end of pregnancy and during breastfeeding (the index period), as reported in parental interviews. Mothers of cases were less likely to report taking iron-specific supplements during the index period (adjusted odds ratio = 0.63, 95% confidence interval: 0.44, 0.91), and they had a lower mean daily iron intake (51.7 (standard deviation, 34.0) mg/day) than mothers of controls (57.1 (standard deviation, 36.6) mg/day; P = 0.03). The highest quintile of iron intake during the index period was associated with reduced ASD risk compared with the lowest (adjusted odds ratio = 0.49, 95% confidence interval: 0.29, 0.82), especially during breastfeeding. Low iron intake significantly interacted with advanced maternal age and metabolic conditions; combined exposures were associated with a 5-fold increased ASD risk. Further studies of this link between maternal supplemental iron and ASD are needed to inform ASD prevention strategies.

PMID: 25249546 [PubMed - as supplied by publisher]

DNA hypermethylation of serotonin transporter gene promoter in drug naïve patients with schizophrenia.

September 24, 2014 - 6:12am
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DNA hypermethylation of serotonin transporter gene promoter in drug naïve patients with schizophrenia.

Schizophr Res. 2014 Feb;152(2-3):373-80

Authors: Abdolmaleky HM, Nohesara S, Ghadirivasfi M, Lambert AW, Ahmadkhaniha H, Ozturk S, Wong CK, Shafa R, Mostafavi A, Thiagalingam S

Abstract
INTRODUCTION: Dysfunctional serotonin signaling has been linked to the pathogenesis of autism, obsessive compulsive disorder, mood disorders and schizophrenia. While the hypo-activity of serotonin signaling is involved in the pathogenesis of depression, anxiety and obsessive compulsive disorder; LSD, an agonist of serotonin type 2 receptor (5-HTR2A) induces psychosis. Therefore, anxiety and depressive disorders are treated by SSRIs which inhibit serotonin transporter (5-HTT) while psychotic disorders are controlled by drugs that block serotonin and/or dopamine receptors. Since genetic polymorphisms and epigenetic dysregulation of 5-HTT are involved in the pathogenesis of mental diseases, we analyzed DNA methylation of 5-HTT promoter in post-mortem brains and saliva samples of patients with schizophrenia (SCZ) and bipolar disorder (BD) to evaluate its potential application as a diagnostic and/or therapeutic biomarker in SCZ and BD.
METHODS: Whole genome DNA methylation profiling was performed for a total of 24 samples (including two saliva samples) using the Illumina 27K (for 12 samples) and 450K DNA methylation array platform (for another 12 samples), followed by bisulfite sequencing to identify candidate CpGs for further analysis. Quantitative methylation specific PCR (qMSP) was used to assess the degree of CpG methylation of 5-HTT promoter in 105 post-mortem brains (35 controls, 35 SCZ and 35 BD) and 100 saliva samples (30 controls, 30 SCZ, 20 BD and 20 first degree relatives of SCZ or BD). The U133 2.0 Plus Human Transcriptome array for a total of 30 post-mortem brain samples (each group 10) followed by quantitative real-time PCR was used to study 5-HTT expression in 105 post-mortem brain samples.
RESULTS: The qMSP analysis for 5-HTT promoter region showed DNA hypermethylation in post-mortem brain samples of SCZ patients (~30%), particularly in drug free patients (~60%, p=0.04). Similarly, there was a trend for DNA hypermethylation in antipsychotic free BD patients (~50%, p=0.066). qMSP analysis of DNA extracted from the saliva samples also exhibited hypermethylation of 5-HTT promoter in patients with SCZ (~30%, p=0.039), which was more significant in drug naïve SCZ patients (>50%, p=0.0025). However, the difference was not significant between the controls and unaffected first degree relatives of patients with SCZ (p=0.37) and versus patients using antipsychotic drugs (p=0.2). The whole genome transcriptome analysis of post-mortem brain samples showed reduced expression of 5-HTT in SCZ compared to the control subjects (~50%, p=0.008), confirmed by quantitative real-time PCR analysis (~40%, p=0.035) which was more significant in drug free SCZ patients (~70%, p=0.022).
CONCLUSION: A correlation between reduction in 5-HTT expression and DNA hypermethylation of the 5-HTT promoter in drug naïve SCZ patients suggests that an epigenetically defined hypo-activity of 5-HTT may be linked to SCZ pathogenesis. Furthermore, this epigenetic mark in DNA extracted from saliva can be considered as one of the key determinants in a panel of diagnostic and/or therapeutic biomarkers for SCZ.

PMID: 24411530 [PubMed - indexed for MEDLINE]

SCAMP5 plays a critical role in synaptic vesicle endocytosis during high neuronal activity.

September 23, 2014 - 6:01am
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SCAMP5 plays a critical role in synaptic vesicle endocytosis during high neuronal activity.

J Neurosci. 2014 Jul 23;34(30):10085-95

Authors: Zhao H, Kim Y, Park J, Park D, Lee SE, Chang I, Chang S

Abstract
Secretory carrier membrane protein 5 (SCAMP5), a recently identified candidate gene for autism, is brain specific and highly abundant in synaptic vesicles (SVs), but its function is currently unknown. Here, we found that knockdown (KD) of endogenous SCAMP5 by SCAMP5-specific shRNAs in cultured rat hippocampal neurons resulted in a reduction in total vesicle pool size as well as in recycling pool size, but the recycling/resting pool ratio was significantly increased. SCAMP5 KD slowed endocytosis after stimulation, but impaired it severely during strong stimulation. We also found that KD dramatically lowered the threshold of activity at which SV endocytosis became unable to compensate for the ongoing exocytosis occurring during a stimulus. Reintroducing shRNA-resistant SCAMP5 reversed these endocytic defects. Therefore, our results suggest that SCAMP5 functions during high neuronal activity when a heavy load is imposed on endocytosis. Our data also raise the possibility that the reduction in expression of SCAMP5 in autistic patients may be related to the synaptic dysfunction observed in autism.

PMID: 25057210 [PubMed - indexed for MEDLINE]

Severity of manifestations in tuberous sclerosis complex in relation to genotype.

September 23, 2014 - 6:01am
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Severity of manifestations in tuberous sclerosis complex in relation to genotype.

Epilepsia. 2014 Jul;55(7):1025-9

Authors: Kothare SV, Singh K, Chalifoux JR, Staley BA, Weiner HL, Menzer K, Devinsky O

Abstract
OBJECTIVE: Patients with tuberous sclerosis complex (TSC) commonly present with significant neurologic deficits, including seizures, autism, and intellectual disability. Previous evidence suggests that the TSC2 mutation genotype may be associated with a more severe disease phenotype. This study evaluates the association of the TSC1 and TSC2 genotype with patient and disease characteristics in a retrospective review of a large TSC Natural History Database consisting of 919 patients with TSC.
METHODS: Univariate logistic regression was conducted to evaluate the association of the TSC1 and TSC2 gene mutations with patient and disease characteristics.
RESULTS: As compared to patients with the TSC1 mutation, patients with the TSC2 mutation were younger (p = 0.02), more likely to have partial epilepsy (odds ratio (OR) 1.74, p = 0.0015), complex partial seizures (OR 2.03, p = 0.02), infantile spasms (IS) (OR 1.67, p = 0.01), subependymal giant-cell astrocytomas (SEGAs) (OR 1.64, p = 0.01), and intellectual disability (OR 2.90, p = 0.0002).
SIGNIFICANCE: The clinical presentation of TSC is highly variable and not well understood. Our findings confirm and supplement existing literature that TSC2 mutation is likely to be associated with a more severe, earlier presenting TSC phenotype, including infantile spasms.

PMID: 24917535 [PubMed - indexed for MEDLINE]

Genotype/phenotype in tuberous sclerosis complex: associations with clinical and radiologic manifestations.

September 23, 2014 - 6:01am
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Genotype/phenotype in tuberous sclerosis complex: associations with clinical and radiologic manifestations.

Epilepsia. 2014 Jul;55(7):1020-4

Authors: Kothare SV, Singh K, Hochman T, Chalifoux JR, Staley BA, Weiner HL, Menzer K, Devinsky O

Abstract
OBJECTIVES: Patients with tuberous sclerosis complex (TSC) frequently have autism spectrum disorders and neuropsychiatric disorders. Subependymal giant cell astrocytomas (SEGAs) have been reported to occur in 5-20% of patients with TSC; however, the relationship between SEGAs and neuropsychiatric disorders in TSC remains unknown. We utilized a large multicenter database to study associations between SEGAs and neuropsychiatric disorders in patients with TSC.
METHODS: Associations between the presence of SEGAs and neuropsychiatric disorders were examined in a retrospective review of 916 patients enrolled in the TSC Natural History Database Project (Tuberous Sclerosis Alliance).
RESULTS: Among the 916 TSC patients, 226 had SEGAs (25%) and 155 had autism spectrum disorder (ASD) (17%). Compared to patients without SEGAs, patients with SEGAs were 1.83 (95% confidence interval [CI] 1.26-2.66) times more likely to have ASD. No significant relationship was found between SEGAs and intellectual disability, attention-deficit/hyperactive disorder, or major depressive disorder.
SIGNIFICANCE: The clinical presentation of TSC is highly variable and not well understood. These data show that SEGAs are associated with ASD in patients with TSC, suggesting that the pathologic changes leading to SEGA formation may also predispose patients to ASD.

PMID: 24754401 [PubMed - indexed for MEDLINE]

[Epigenome: what we learned from Rett syndrome, a neurological disease caused by mutation of a methyl-CpG binding protein].

September 23, 2014 - 6:01am
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[Epigenome: what we learned from Rett syndrome, a neurological disease caused by mutation of a methyl-CpG binding protein].

Rinsho Shinkeigaku. 2013;53(11):1339-41

Authors: Kubota T

Abstract
Epigenome is defined as DNA and histone modification-dependent gene regulation system. Abnormalities in this system are known to cause various neuro-developmental diseases. We recently reported that neurological symptoms of Rett syndrome, which is an autistic disorder caused by mutations in methyl-CpG binding protein 2 (MeCP2), was associated with failure of epigenomic gene regulation in neuronal cells, and that clinical differences in the identical twins with Rett syndrome in the differences in DNA methylation in neuronal genes, but not caused by DNA sequence differences. Since central nervus system requires precise gene regulation, neurological diseases including Alzheimer and Parkinson diseases may be caused by acquired DNA modification (epigenomic) changes that results in aberrant gene regulation as well as DNA sequence changes congenitally occurred (mutation).

PMID: 24291980 [PubMed - indexed for MEDLINE]

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