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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]

The Kvβ2 subunit of voltage-gated potassium channels is interacting with ProSAP2/Shank3 in the PSD.

September 23, 2014 - 6:01am
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The Kvβ2 subunit of voltage-gated potassium channels is interacting with ProSAP2/Shank3 in the PSD.

Neuroscience. 2014 Mar 7;261:133-43

Authors: Proepper C, Putz S, Russell R, Boeckers TM, Liebau S

Abstract
The postsynaptic density is an electron dense meshwork composed of a variety of molecules facilitating neuronal signal transmission. ProSAP2/Shank3 represents a crucial player at postsynaptic sites, assembling large multimeric platforms and anchoring numerous other molecules, thereby linking the functional synapse with the cytoskeleton. ProSAP2/Shank3 is also implicated in the pathogenesis of numerous diseases, including autism spectrum disorders. KvBeta2 (Kvβ2) on the other hand serves as a regulatory subunit of voltage-gated potassium channels. Kvβ2 is located at various sites in the neuron including the axon (binding to Kv1.2), the dendrites (binding to Kv4.2) and the synapse. Binding of Kvβ2 to either Kv1.2 or Kv4 modulates not only the channel conformation but directs targeting of the channel protein complex to distinct loci within the cell. Thus an interaction between ProSAP2 and Kvβ2 could have important roles at diverse cellular compartments and moreover during maturation stages. We report here on the direct protein-protein interaction of the postsynaptic density anchoring molecule ProSAP2 and the potassium channel subunit Kvβ2, initially identified in a yeast-two-hybrid-screen. Furthermore, we characterize this interaction at synapses using primary hippocampal neurons in vitro.

PMID: 24211303 [PubMed - indexed for MEDLINE]

Polymorphisms in the oxytocin receptor gene are associated with the development of psychopathy.

September 23, 2014 - 6:01am
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Polymorphisms in the oxytocin receptor gene are associated with the development of psychopathy.

Dev Psychopathol. 2014 Feb;26(1):21-31

Authors: Dadds MR, Moul C, Cauchi A, Dobson-Stone C, Hawes DJ, Brennan J, Urwin R, Ebstein RE

Abstract
The co-occurrence of child conduct problems (CPs) and callous-unemotional (CU) traits confers risk for psychopathy. The oxytocin (OXT) system is a likely candidate for involvement in the development of psychopathy. We tested variations in the OXT receptor gene (OXTR) in CP children and adolescents with varying levels of CU traits. Two samples of Caucasian children, aged 4-16 years, who met DSM criteria for disruptive behavior problems and had no features of autism spectrum disorder, were stratified into low versus high CU traits. Measures were the frequencies of nine candidate OXTR polymorphisms (single nucleotide polymorphisms). In Sample 1, high CU traits were associated with single nucleotide polymorphism rs1042778 in the 3' untranslated region of OXTR and the CGCT haplotype of rs2268490, rs2254298, rs237889, and rs13316193. The association of rs1042778 was replicated in the second rural sample and held across gender and child versus adolescent age groups. We conclude that polymorphic variation of the OXTR characterizes children with high levels of CU traits and CPs. The results are consistent with a hypothesized role of OXT in the developmental antecedents of psychopathy, particularly the differential amygdala activation model of psychopathic traits, and add genetic evidence that high CU traits specify a distinct subgroup within CP children.

PMID: 24059750 [PubMed - indexed for MEDLINE]

Excess of runs of homozygosity is associated with severe cognitive impairment in intellectual disability.

September 19, 2014 - 7:41am

Excess of runs of homozygosity is associated with severe cognitive impairment in intellectual disability.

Genet Med. 2014 Sep 18;

Authors: Gandin I, Faletra F, Faletra F, Carella M, Pecile V, Ferrero GB, Biamino E, Palumbo P, Palumbo O, Bosco P, Romano C, Belcaro C, Vozzi D, d'Adamo AP

Abstract
Purpose:The harmful effects of inbreeding are well known by geneticists, and several studies have already reported cases of intellectual disability caused by recessive variants in consanguineous families. Nevertheless, the effects of inbreeding on the degree of intellectual disability are still poorly investigated. Here, we present a detailed analysis of the homozygosity regions in a cohort of 612 patients with intellectual disabilities of different degrees.Methods:We investigated (i) the runs of homozygosity distribution between syndromic and nonsyndromic ID (ii) the effect of runs of homozygosity on the ID degree, using the intelligence quotient score.Results:Our data revealed no significant differences in the first analysis; instead we detected significantly larger runs of homozygosity stretches in severe ID compared to nonsevere ID cases (P = 0.007), together with an increase of the percentage of genome covered by runs of homozygosity (P = 0.03).Conclusion:In accord with the recent findings regarding autism and other neurological disorders, this study reveals the important role of autosomal recessive variants in intellectual disability. The amount of homozygosity seems to modulate the degree of cognitive impairment despite the intellectual disability cause.Genet Med advance online publication 18 September 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.118.

PMID: 25232855 [PubMed - as supplied by publisher]

De novo TBR1 mutations in sporadic autism disrupt protein functions.

September 19, 2014 - 7:41am

De novo TBR1 mutations in sporadic autism disrupt protein functions.

Nat Commun. 2014;5:4954

Authors: Deriziotis P, O'Roak BJ, Graham SA, Estruch SB, Dimitropoulou D, Bernier RA, Gerdts J, Shendure J, Eichler EE, Fisher SE

Abstract
Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.

PMID: 25232744 [PubMed - as supplied by publisher]

Autism: pinpointing common deficits.

September 19, 2014 - 7:41am
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Autism: pinpointing common deficits.

Nat Rev Neurosci. 2014 Aug;15(8):493

Authors: Yates D

PMID: 25158355 [PubMed - indexed for MEDLINE]

Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors.

September 19, 2014 - 7:41am
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Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors.

Cell. 2014 Jul 3;158(1):198-212

Authors: Rothwell PE, Fuccillo MV, Maxeiner S, Hayton SJ, Gokce O, Lim BK, Fowler SC, Malenka RC, Südhof TC

Abstract
In humans, neuroligin-3 mutations are associated with autism, whereas in mice, the corresponding mutations produce robust synaptic and behavioral changes. However, different neuroligin-3 mutations cause largely distinct phenotypes in mice, and no causal relationship links a specific synaptic dysfunction to a behavioral change. Using rotarod motor learning as a proxy for acquired repetitive behaviors in mice, we found that different neuroligin-3 mutations uniformly enhanced formation of repetitive motor routines. Surprisingly, neuroligin-3 mutations caused this phenotype not via changes in the cerebellum or dorsal striatum but via a selective synaptic impairment in the nucleus accumbens/ventral striatum. Here, neuroligin-3 mutations increased rotarod learning by specifically impeding synaptic inhibition onto D1-dopamine receptor-expressing but not D2-dopamine receptor-expressing medium spiny neurons. Our data thus suggest that different autism-associated neuroligin-3 mutations cause a common increase in acquired repetitive behaviors by impairing a specific striatal synapse and thereby provide a plausible circuit substrate for autism pathophysiology.

PMID: 24995986 [PubMed - indexed for MEDLINE]

How far can mice carry autism research?

September 19, 2014 - 7:41am
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How far can mice carry autism research?

Cell. 2014 Jul 3;158(1):13-4

Authors: Hyman SE

Abstract
In the face of growing controversy about the utility of genetic mouse models of human disease, Rothwell et al. report on a shared mechanism by which two different neuroligin-3 mutations, associated with autism spectrum disorders in humans, produce an enhancement in motor learning. The open question is how much we can learn about human ills from such models.

PMID: 24995974 [PubMed - indexed for MEDLINE]

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