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Predicting future discoveries from current scientific literature.

May 13, 2015 - 7:06am
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Predicting future discoveries from current scientific literature.

Methods Mol Biol. 2014;1159:159-68

Authors: Petrič I, Cestnik B

Abstract
Knowledge discovery in biomedicine is a time-consuming process starting from the basic research, through preclinical testing, towards possible clinical applications. Crossing of conceptual boundaries is often needed for groundbreaking biomedical research that generates highly inventive discoveries. We demonstrate the ability of a creative literature mining method to advance valuable new discoveries based on rare ideas from existing literature. When emerging ideas from scientific literature are put together as fragments of knowledge in a systematic way, they may lead to original, sometimes surprising, research findings. If enough scientific evidence is already published for the association of such findings, they can be considered as scientific hypotheses. In this chapter, we describe a method for the computer-aided generation of such hypotheses based on the existing scientific literature. Our literature-based discovery of NF-kappaB with its possible connections to autism was recently approved by scientific community, which confirms the ability of our literature mining methodology to accelerate future discoveries based on rare ideas from existing literature.

PMID: 24788267 [PubMed - indexed for MEDLINE]

Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders.

May 13, 2015 - 7:06am
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Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders.

Brain Res. 2014 Sep 11;1580:199-218

Authors: Francis SM, Sagar A, Levin-Decanini T, Liu W, Carter CS, Jacob S

Abstract
Oxytocin (OT) and arginine vasopressin (AVP) are two small, related neuropeptide hormones found in many mammalian species, including humans. Dysregulation of these neuropeptides have been associated with changes in behavior, especially social interactions. We review how the OT and AVP systems have been investigated in Autism Spectrum Disorder (ASD), Prader-Willi Syndrome (PWS), Williams Syndrome (WS) and Fragile X syndrome (FXS). All of these neurodevelopmental disorders (NDD) are marked by social deficits. While PWS, WS and FXS have identified genetic mutations, ASD stems from multiple genes with complex interactions. Animal models of NDD are invaluable for studying the role and relatedness of OT and AVP in the developing brain. We present data from a FXS mouse model affecting the fragile X mental retardation 1 (Fmr1) gene, resulting in decreased OT and AVP staining cells in some brain regions. Reviewing the research about OT and AVP in these NDD suggests that altered OT pathways may be downstream from different etiological factors and perturbations in development. This has implications for ongoing studies of the therapeutic application of OT in NDD. This article is part of a Special Issue entitled Oxytocin and Social Behav.

PMID: 24462936 [PubMed - indexed for MEDLINE]

A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia.

May 13, 2015 - 7:06am
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A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia.

Clin Genet. 2014 Sep;86(3):276-81

Authors: Roos L, Fang M, Dali C, Jensen H, Christoffersen N, Wu B, Zhang J, Xu R, Harris P, Xu X, Grønskov K, Tümer Z

Abstract
Anomalies of eye development can lead to the rare eye malformations microphthalmia and anophthalmia (small or absent ocular globes), which are genetically very heterogeneous. Several genes have been associated with microphthalmia and anophthalmia, and exome sequencing has contributed to the identification of new genes. Very recently, homozygous variations within ALDH1A3 have been associated with autosomal recessive microphthalmia with or without cysts or coloboma, and with variable subphenotypes of developmental delay/autism spectrum disorder in eight families. In a consanguineous family where three of the five siblings were affected with microphthalmia/coloboma, we identified a novel homozygous missense mutation in ALDH1A3 using exome sequencing. Of the three affected siblings, one had intellectual disability and one had intellectual disability and autism, while the last one presented with normal development. This study contributes further to the description of the clinical spectrum associated with ALDH1A3 mutations, and illustrates the interfamilial clinical variation observed in individuals with ALDH1A3 mutations.

PMID: 24024553 [PubMed - indexed for MEDLINE]

Human induced pluripotent stem cells: now open to discovery.

May 12, 2015 - 8:45am
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Human induced pluripotent stem cells: now open to discovery.

Cell Stem Cell. 2014 Jul 3;15(1):4-6

Authors: Durak O, Tsai LH

Abstract
Human induced pluripotent stem cells represent a promising tool for investigating the underlying causes of disease; however, this potential currently remains unfulfilled. In this issue of Cell Stem Cell, Yoon et al. (2014) used iPSCs derived from patients harboring common genetic risk variants as the starting point to discover novel insights into disease pathology.

PMID: 24996162 [PubMed - indexed for MEDLINE]

Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions.

May 12, 2015 - 8:45am
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Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions.

Am J Psychiatry. 2014 Nov 1;171(11):1206-13

Authors: Risch N, Hoffmann TJ, Anderson M, Croen LA, Grether JK, Windham GC

Abstract
OBJECTIVE: This study was designed to examine the pattern of familial recurrence of autism spectrum disorder (ASD) in terms of genetic and environmental contributions related to timing of birth.
METHOD: The authors linked California Department of Developmental Services records with state birth certificates to identify all siblings and half siblings of individuals affected with ASD born between 1990 and 2003. A total of 6,616 full siblings, 644 maternal half siblings, and 299 paternal half siblings born after ASD index cases were used to calculate recurrence risks. Control families, identified through matching to cases, were included for comparison (a total of 29,384 siblings).
RESULTS: The overall sibling recurrence risk was 10.1%, compared with a prevalence of 0.52% in siblings of controls. The recurrence risk in second-born children was higher (11.5%) than in later-born siblings (7.3%); a similar pattern was observed for maternal half siblings (6.5% for second-born compared with 3.0% for later-born siblings; 4.8% overall). The recurrence risk was significantly higher for siblings who immediately followed the index case in birth order compared with those later in birth order. The recurrence risk for paternal half siblings (2.3%) was half the overall recurrence risk for maternal half siblings but was similar to that for later-born maternal half siblings. An exponential effect of short interbirth interval was observed, with the recurrence risk reaching 14.4% for an interbirth interval of 18 months or less, compared with 6.8% for an interval of 4 years or more. An identical phenomenon was observed in maternal half siblings.
CONCLUSIONS: The results support genetic susceptibility in the familial recurrence of ASD along with factors related to timing of birth.

PMID: 24969362 [PubMed - indexed for MEDLINE]

Deletion of TRIM32 protects mice from anxiety- and depression-like behaviors under mild stress.

May 12, 2015 - 8:45am
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Deletion of TRIM32 protects mice from anxiety- and depression-like behaviors under mild stress.

Eur J Neurosci. 2014 Aug;40(4):2680-90

Authors: Ruan CS, Wang SF, Shen YJ, Guo Y, Yang CR, Zhou FH, Tan LT, Zhou L, Liu JJ, Wang WY, Xiao ZC, Zhou XF

Abstract
Chronic stress causes a variety of psychiatric disorders such as anxiety and depression, but its mechanism is not well understood. Tripartite motif-containing protein 32 (TRIM32) was strongly associated with autism spectrum disorder, attention deficit hyperactivity disorder, anxiety and obsessive compulsive disorder based on a study of copy number variation, and deletion of TRIM32 increased neural proliferation and reduced apoptosis. Here, we propose that TRIM32 is involved in chronic stress-induced affective behaviors. Using a chronic unpredictable mild stress mouse depression model, we studied expression of TRIM32 in brain tissue samples and observed behavioral changes in Trim32 knockout mice. The results showed that TRIM32 protein but not its mRNA was significantly reduced in hippocampus in a time-dependent manner within 8 weeks of chronic stress. These stress-induced affective behaviors and reduction of TRIM32 protein expression were significantly reversed by antidepressant fluoxetine treatment. In addition, Trim32 knockout mice showed reduced anxiety and depressive behaviors and hyperactivities compared with Trim32 wild-type mice under normal and mild stress conditions. We conclude that TRIM32 plays important roles in regulation of hyperactivities and positively regulates the development of anxiety and depression disorders induced by chronic stress.

PMID: 24839933 [PubMed - indexed for MEDLINE]

Common EIF4E variants modulate risk for autism spectrum disorders in the high-functioning range.

May 12, 2015 - 8:45am
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Common EIF4E variants modulate risk for autism spectrum disorders in the high-functioning range.

J Neural Transm. 2014 Sep;121(9):1107-16

Authors: Waltes R, Gfesser J, Haslinger D, Schneider-Momm K, Biscaldi M, Voran A, Freitag CM, Chiocchetti AG

Abstract
The genetic architecture of Autism Spectrum Disorders (ASD) is complex. Common genetic variation has especially been related to high-functioning ASD. In addition, some studies favoured analysis of strictly diagnosed autism individuals, which resulted in more robust findings than the combined analysis of all spectrum individuals. Functional variants modulating EIF4E expression have previously been indicated as risk factors for ASD. Pharmacological modulation of glutamate receptors which regulate EIF4E activity resulted in reduced repetitive behaviours in human and animal studies. Based on these findings, we tested common EIF4E variants for association with overall ASD, with strict autism and with the strict high-functioning autism (strict HFA) subgroup, and their effect on repetitive and/or stereotypic behaviour. We observed over-transmission of rs13109000G in the strict HFA and the strict autism cohort but not in the larger ASD cohort. We report protective effects for the minor allele of rs4699369T on stereotyped and ritualized behaviour in the overall ASD cohort, the strict autism but not in the strict HFA group. In addition, a protective role for rs4699369T and a risk effect of rs12498533G on hand and finger mannerisms was observed. These results need to be replicated in larger ASD and strict autism samples. The predicted impact on transcription through the ASD associated EIF4E variants rs4699369T and rs12498533G as well as the association of the EIF4E interaction partners FMRP and CYFIP1 with ASD point to an mRNA mediated pathomechanism for ASD.

PMID: 24818597 [PubMed - indexed for MEDLINE]

Phenotype profiling of patients with intellectual disability and copy number variations.

May 12, 2015 - 8:45am
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Phenotype profiling of patients with intellectual disability and copy number variations.

Eur J Paediatr Neurol. 2014 Sep;18(5):558-66

Authors: Roselló M, Martínez F, Monfort S, Mayo S, Oltra S, Orellana C

Abstract
BACKGROUND: Nowadays the microarray technology allows whole-genome analysis with a high resolution and performance for the genetic diagnosis in any patient with intellectual disability or autism spectrum disorder. However in the immediate future, with the development of massive sequencing systems for application at clinical diagnosis, it will be necessary to have clinical criteria to guide studies.
AIM: To perform an exhaustive clinical definition of patients with pathogenic copy number variations in order to establish the clinical criteria most suggestive of this kind of genomic rearrangements.
METHOD: We designed and implemented a database to collect 190 different clinical variables (pregnancy, neonatal, facial dysmorphism, congenital anomalies, neurological features and family history) in a series of 246 patients, with developmental delay/intellectual disability. All cases were studied with array comparative genomic hybridization.
RESULTS: We have found a pathogenic genomic imbalance in 73 patients. Frequency analysis of all clinical variables showed that growth disorder, abnormalities of hands, low-set ears and hypertelorism are the more frequent features among patients with genomic rearrangements. However other clinical features, such as genital abnormalities and aggressiveness, are more specifically associated with pathogenic copy number variations in spite of their low frequencies in the overall series, yielding higher statistical significance values than other traits.
CONCLUSIONS: The genotype-phenotype comparison may be useful to set in the future the main clinical manifestations associated with deletions, duplications and unbalanced translocations. Theses analyses will improve the clinical indications and protocols to implement genomic arrays in the genetic study of patients with neurodevelopment disorders.

PMID: 24815074 [PubMed - indexed for MEDLINE]

Impaired hippocampus-dependent spatial flexibility and sociability represent autism-like phenotypes in GluK2 mice.

May 12, 2015 - 8:45am
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Impaired hippocampus-dependent spatial flexibility and sociability represent autism-like phenotypes in GluK2 mice.

Hippocampus. 2014 Sep;24(9):1059-69

Authors: Micheau J, Vimeney A, Normand E, Mulle C, Riedel G

Abstract
Autism is a complex neurodevelopmental disorder with high heritability. grik2 (which encodes the GluK2 subunit of kainate receptors) has been identified as a susceptibility gene in Autism Spectrum Disorders (ASD), but its role in the core and associated symptoms of ASD still remains elusive. We used mice lacking GluK2 (GluK2 KO) to examine their endophenotype with a view to modeling aspects of autism, including social deficits, stereotyped and repetitive behavior and decreased cognitive abilities. Anxiety was recorded in the elevated plus maze, social behavior in a three-chamber apparatus, and cognition in different water maze protocols. Deletion of the GluK2 gene reduced locomotor activity and sociability as indicated by the social interaction task. In addition, GluK2 KO mice learnt to locate a hidden platform in a water maze surrounded by a curtain with hanging cues faster than wild-type mice. They maintained a bias toward the target quadrant when some of these cues were removed, at which point wild-types orthogonalized the behavior and showed no memory. However, GluK2 KO mice were impaired in spatial reversal learning. These behavioral data together with previously published electrophysiology showing severe anomalies in CA3 network activity, suggest a computational shift in this network for enhanced propensity of pattern completion that would explain the loss of behavioral flexibility in GluK2 KO mice. Although a single mutation cannot recapitulate the entire core symptoms of ASD, our data provide evidence for glutamatergic dysfunction underlying a number of social- and cognition-related phenotypes relevant to ASD.

PMID: 24753134 [PubMed - indexed for MEDLINE]

Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders.

May 12, 2015 - 8:45am
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Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders.

Hum Mol Genet. 2014 Sep 15;23(R1):R1-8

Authors: Burrage LC, Nagamani SC, Campeau PM, Lee BH

Abstract
Branched-chain amino acid (BCAA) metabolism plays a central role in the pathophysiology of both rare inborn errors of metabolism and the more common multifactorial diseases. Although deficiency of the branched-chain ketoacid dehydrogenase (BCKDC) and associated elevations in the BCAAs and their ketoacids have been recognized as the cause of maple syrup urine disease (MSUD) for decades, treatment options for this disorder have been limited to dietary interventions. In recent years, the discovery of improved leucine tolerance after liver transplantation has resulted in a new therapeutic strategy for this disorder. Likewise, targeting the regulation of the BCKDC activity may be an alternative potential treatment strategy for MSUD. The regulation of the BCKDC by the branched-chain ketoacid dehydrogenase kinase has also been implicated in a new inborn error of metabolism characterized by autism, intellectual disability and seizures. Finally, there is a growing body of literature implicating BCAA metabolism in more common disorders such as the metabolic syndrome, cancer and hepatic disease. This review surveys the knowledge acquired on the topic over the past 50 years and focuses on recent developments in the field of BCAA metabolism.

PMID: 24651065 [PubMed - indexed for MEDLINE]

Neural bases of Theory of Mind in children with autism spectrum disorders and children with conduct problems and callous-unemotional traits.

May 12, 2015 - 8:45am
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Neural bases of Theory of Mind in children with autism spectrum disorders and children with conduct problems and callous-unemotional traits.

Dev Sci. 2014 Sep;17(5):786-96

Authors: O'Nions E, Sebastian CL, McCrory E, Chantiluke K, Happé F, Viding E

Abstract
Individuals with autism spectrum disorders (ASD) have difficulty understanding other minds (Theory of Mind; ToM), with atypical processing evident at both behavioural and neural levels. Individuals with conduct problems and high levels of callous-unemotional (CU) traits (CP/HCU) exhibit reduced responsiveness to others' emotions and difficulties interacting with others, but nonetheless perform normally in experimental tests of ToM. The present study aimed to examine the neural underpinnings of ToM in children (aged 10-16) with ASD (N = 16), CP/HCU (N = 16) and typically developing (TD) controls (N = 16) using a non-verbal cartoon vignette task. Whilst individuals with ASD were predicted to show reduced fMRI responses across regions involved in ToM processing, CP/HCU individuals were predicted to show no differences compared with TD controls. The analyses indicated that neural responses did not differ between TD and CP/HCU groups during ToM. TD and CP/HCU children exhibited significantly greater medial prefrontal cortex responses during ToM than did the ASD group. Within the ASD group, responses in medial prefrontal cortex and right temporoparietal junction (TPJ) correlated with symptom severity as measured by the Autism Diagnostic Observation Schedule (ADOS). Findings suggest that although both ASD and CP/HCU are characterized by social difficulties, only children with ASD display atypical neural processing associated with ToM.

PMID: 24636205 [PubMed - indexed for MEDLINE]

Disrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron activity through cAMP regulation of transient receptor potential C and small-conductance K+ channels.

May 12, 2015 - 8:45am
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Disrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron activity through cAMP regulation of transient receptor potential C and small-conductance K+ channels.

Biol Psychiatry. 2014 Sep 15;76(6):476-85

Authors: El-Hassar L, Simen AA, Duque A, Patel KD, Kaczmarek LK, Arnsten AF, Yeckel MF

Abstract
BACKGROUND: Disrupted in schizophrenia 1 (DISC1) is a protein implicated in schizophrenia, bipolar disorder, major depressive disorder, and autism. To date, most of research examining DISC1 function has focused on its role in neurodevelopment, despite its presence throughout life. DISC1 also regulates cyclic adenosine monophosphate (cAMP) signaling by increasing type 4 phosphodiesterase catabolism of cAMP when cAMP concentrations are high. In this study, we tested the hypothesis that DISC1, through its regulation of cAMP, modulates I-SK and I-TRPC channel-mediated ionic currents that we have shown previously to regulate the activity of mature prefrontal cortical pyramidal neurons.
METHODS: We used patch-clamp recordings in prefrontal cortical slices from adult rats in which DISC1 function was reduced in vivo by short hairpin RNA viral knockdown or in vitro by dialysis of DISC1 antibodies.
RESULTS: We found that DISC1 disruption resulted in an increase of metabotropic glutamate receptor-induced intracellular calcium (Ca2+) waves, small-conductance K+ (SK)-mediated hyperpolarization and a decrease of transient receptor potential C (TRPC)-mediated sustained depolarization. Consistent with a role for DISC1 in regulation of cAMP signaling, forskolin-induced cAMP production also increased intracellular Ca2+ waves, I-SK and decreased I-TRPC. Lastly, inhibiting cAMP generation with guanfacine, an α2A-noradrenergic agonist, normalized the function of SK and TRPC channels.
CONCLUSIONS: Based on our findings, we propose that diminished DISC1 function, such as occurs in some mental disorders, can lead to the disruption of normal patterns of prefrontal cortex activity through the loss of cAMP regulation of metabotropic glutamate receptor-mediated intracellular Ca2+ waves, SK and TRPC channel activity.

PMID: 24560582 [PubMed - indexed for MEDLINE]

Cognitive deficit and autism spectrum disorders: prospective diagnosis by array CGH.

May 12, 2015 - 8:45am
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Cognitive deficit and autism spectrum disorders: prospective diagnosis by array CGH.

Pathology. 2014 Jan;46(1):41-5

Authors: Nicholl J, Waters W, Mulley JC, Suwalski S, Brown S, Hull Y, Barnett C, Haan E, Thompson EM, Liebelt J, Mcgregor L, Harbord MG, Entwistle J, Munt C, White D, Chitti A, Baulderstone D, Ketteridge D, Array Referral Consortium, Friend K, Bain SM, Yu S

Abstract
The aim of this study was to determine prospectively the frequency of pathogenic chromosomal microdeletions and microduplications in a large group of referred patients with developmental delay (DD), intellectual disability (ID) or autism spectrum disorders (ASD) within a genetic diagnostic service. First tier testing was applied using a standardised oligo-array comparative genomic hybridization (CGH) platform, replacing conventional cytogenetic testing that would have been used in the past. Copy number variants (CNVs) found to be responsible for the clinical condition on the request form could all be subdivided into three groups: well established pathogenic microdeletion/microduplication/aneuploidy syndromes, predicted pathogenic CNVs as interpreted by the laboratory, and recently established pathogenic disease susceptibility CNVs. Totalled from these three groups, with CNVs of uncertain significance excluded, detection rates were: DD (13.0%), ID (15.6%), ASD (2.3%), ASD with DD (8.2%), ASD with ID (12.7%) and unexplained epilepsy with DD, ID and ASD (10.9%). The greater diagnostic sensitivity arising from routine application of array CGH, compared with previously used conventional cytogenetics, outweighs the interpretative issues for the reporting laboratory and referring clinician arising from detection of CNVs of uncertain significance. Precise determination of any previously hidden molecular defect responsible for the patient's condition is translated to improved genetic counselling.

PMID: 24300712 [PubMed - indexed for MEDLINE]

Response to 'Predicting the diagnosis of autism spectrum disorder using gene pathway analysis'.

May 12, 2015 - 8:45am
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Response to 'Predicting the diagnosis of autism spectrum disorder using gene pathway analysis'.

Mol Psychiatry. 2014 Aug;19(8):859-61

Authors: Robinson EB, Howrigan D, Yang J, Ripke S, Anttila V, Duncan LE, Jostins L, Barrett JC, Medland SE, MacArthur DG, Breen G, O'Donovan MC, Wray NR, Devlin B, Daly MJ, Visscher PM, Sullivan PF, Neale BM

PMID: 24145379 [PubMed - indexed for MEDLINE]

Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.

May 12, 2015 - 8:45am
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Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.

Mol Psychiatry. 2014 Aug;19(8):872-9

Authors: Kenny EM, Cormican P, Furlong S, Heron E, Kenny G, Fahey C, Kelleher E, Ennis S, Tropea D, Anney R, Corvin AP, Donohoe G, Gallagher L, Gill M, Morris DW

Abstract
Schizophrenia (SZ) and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that may share an underlying pathology suggested by shared genetic risk variants. We sequenced the exonic regions of 215 genes in 147 ASD cases, 273 SZ cases and 287 controls, to identify rare risk mutations. Genes were primarily selected for their function in the synapse and were categorized as: (1) Neurexin and Neuroligin Interacting Proteins, (2) Post-synaptic Glutamate Receptor Complexes, (3) Neural Cell Adhesion Molecules, (4) DISC1 and Interactors and (5) Functional and Positional Candidates. Thirty-one novel loss-of-function (LoF) variants that are predicted to severely disrupt protein-coding sequence were detected among 2 861 rare variants. We found an excess of LoF variants in the combined cases compared with controls (P=0.02). This effect was stronger when analysis was limited to singleton LoF variants (P=0.0007) and the excess was present in both SZ (P=0.002) and ASD (P=0.001). As an individual gene category, Neurexin and Neuroligin Interacting Proteins carried an excess of LoF variants in cases compared with controls (P=0.05). A de novo nonsense variant in GRIN2B was identified in an ASD case adding to the growing evidence that this is an important risk gene for the disorder. These data support synapse formation and maintenance as key molecular mechanisms for SZ and ASD.

PMID: 24126926 [PubMed - indexed for MEDLINE]

Think about it: FMR1 gene mosaicism.

May 12, 2015 - 8:45am
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Think about it: FMR1 gene mosaicism.

J Child Neurol. 2014 Sep;29(9):NP74-7

Authors: Bonarrigo FA, Russo S, Vizziello P, Menni F, Cogliati F, Giorgini V, Monti F, Milani D

Abstract
Fragile X syndrome (FXS) is one of the most frequent causes of mental retardation, intellectual disability, and autism. Most cases are the result of an expansion of the CGG trinucleotide repeat in the 5' untranslated region of the FMR1 gene and the subsequent functional loss of the related protein. We describe the case of a 4-year-old boy who clinically presents mild psychomotor delay without any major clinical dysmorphisms. Molecular analysis of the FMR1 gene showed mosaicism in terms of size and methylation, with one normal and 1 fully mutated allele, which is very rare in this syndrome. Physicians should therefore consider a diagnosis of FXS even if the patient's phenotype is mild. Although rare, diagnosing this condition has important consequences for the patient's rehabilitation and the family planning of parents and relatives.

PMID: 24065579 [PubMed - indexed for MEDLINE]

Common DNA methylation alterations in multiple brain regions in autism.

May 12, 2015 - 8:45am
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Common DNA methylation alterations in multiple brain regions in autism.

Mol Psychiatry. 2014 Aug;19(8):862-71

Authors: Ladd-Acosta C, Hansen KD, Briem E, Fallin MD, Kaufmann WE, Feinberg AP

Abstract
Autism spectrum disorders (ASD) are increasingly common neurodevelopmental disorders defined clinically by a triad of features including impairment in social interaction, impairment in communication in social situations and restricted and repetitive patterns of behavior and interests, with considerable phenotypic heterogeneity among individuals. Although heritability estimates for ASD are high, conventional genetic-based efforts to identify genes involved in ASD have yielded only few reproducible candidate genes that account for only a small proportion of ASDs. There is mounting evidence to suggest environmental and epigenetic factors play a stronger role in the etiology of ASD than previously thought. To begin to understand the contribution of epigenetics to ASD, we have examined DNA methylation (DNAm) in a pilot study of postmortem brain tissue from 19 autism cases and 21 unrelated controls, among three brain regions including dorsolateral prefrontal cortex, temporal cortex and cerebellum. We measured over 485,000 CpG loci across a diverse set of functionally relevant genomic regions using the Infinium HumanMethylation450 BeadChip and identified four genome-wide significant differentially methylated regions (DMRs) using a bump hunting approach and a permutation-based multiple testing correction method. We replicated 3/4 DMRs identified in our genome-wide screen in a different set of samples and across different brain regions. The DMRs identified in this study represent suggestive evidence for commonly altered methylation sites in ASD and provide several promising new candidate genes.

PMID: 23999529 [PubMed - indexed for MEDLINE]

A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CACNA1C in brain.

May 12, 2015 - 8:45am
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A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CACNA1C in brain.

Mol Psychiatry. 2014 Aug;19(8):890-4

Authors: Gershon ES, Grennan K, Busnello J, Badner JA, Ovsiew F, Memon S, Alliey-Rodriguez N, Cooper J, Romanos B, Liu C

Abstract
Timothy Syndrome (TS) is caused by very rare exonic mutations of the CACNA1C gene that produce delayed inactivation of Cav1.2 voltage-gated calcium channels during cellular action potentials, with greatly increased influx of calcium into the activated cells. The major clinical feature of this syndrome is a long QT interval that results in cardiac arrhythmias. However, TS also includes cognitive impairment, autism and major developmental delays in many of the patients. We observed the appearance of bipolar disorder (BD) in a patient with a previously reported case of TS, who is one of the very few patients to survive childhood. This is most interesting because the common single-nucleotide polymorphism (SNP) most highly associated with BD is rs1006737, which we show here is a cis-expression quantitative trait locus for CACNA1C in human cerebellum, and the risk allele (A) is associated with decreased expression. To combine the CACNA1C perturbations in the presence of BD in this patient and in patients with the common CACNA1C SNP risk allele, we would propose that either increase or decrease in calcium influx in excitable cells can be associated with BD. In treatment of BD with calcium channel blocking drugs, we would predict better response in patients without the risk allele, because they have increased CACNA1C expression.

PMID: 23979604 [PubMed - indexed for MEDLINE]

Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients.

May 11, 2015 - 6:54am

Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients.

Brain Dev. 2015 May 6;

Authors: Yang Z, Matsumoto A, Nakayama K, Jimbo EF, Kojima K, Nagata KI, Iwamoto S, Yamagata T

Abstract
BACKGROUND: The genetic background of autism spectrum disorder (ASD) is considered a multi-genetic disorder with high heritability. Autistic children present with a higher prevalence of sleep disorders than has been observed in children with normal development. Some circadian-relevant genes have been associated with ASD (e.g., PER1, PER2, NPAS2, MTNR1A, and MTNR1B).
METHODS: We analyzed 28 ASD patients (14 with sleep disorders and 14 without) and 23 control subjects of Japanese descent. The coding regions of 18 canonical clock genes and clock-controlled genes were sequenced. Detected mutations were verified by direct sequencing analysis, and additional control individuals were screened.
RESULTS: Thirty-six base changes with amino acid changes were detected in 11 genes. Six missense changes were detected only in individuals with ASD with sleep disturbance: p.F498S in TIMELESS, p.S20R in NR1D1, p.R493C in PER3, p.H542R in CLOCK, p.L473S in ARNTL2, and p.A325V in MTNR1B. Six missense changes were detected only in individuals with ASD without sleep disturbance: p.S1241N in PER1, p.A325T in TIMELESS, p.S13T in ARNTL, p.G24E in MTNR1B, p.G24E in PER2, and p.T1177A in PER3. The p.R493C mutation in PER3 was detected in both groups. One missense change, p.P932L in PER2, was detected only in the control group. Mutations in NR1D1, CLOCK, and ARNTL2 were detected only in individuals with ASD with sleep disorder. The prevalence of the mutations detected only single time differed significantly among all ASD patients and controls (p=0.003). Two kinds of mutations detected only in individuals with ASD with sleep disorder, p.F498S in TIMELESS and p.R366Q in PER3, were considered to affect gene function by three different methods: PolyPhen-2, scale-invariant feature transform (SIFT) prediction, and Mutation Taster (www.mutationtaster.org). The mutations p.S20R in NR1D1, p.H542R in CLOCK, p.L473S in ARNTL2, p.A325T in TIMELESS, p.S13T in ARNTL, and p.G24E in PER2 were diagnosed to negatively affect gene function by more than one of these methods.
CONCLUSION: Mutations in circadian-relevant genes affecting gene function are more frequent in patients with ASD than in controls. Circadian-relevant genes may be involved in the psychopathology of ASD.

PMID: 25957987 [PubMed - as supplied by publisher]

Spatiotemporal dynamics of the postnatal developing primate brain transcriptome.

May 9, 2015 - 7:25am

Spatiotemporal dynamics of the postnatal developing primate brain transcriptome.

Hum Mol Genet. 2015 May 7;

Authors: Bakken TE, Miller JA, Luo R, Bernard A, Bennett JL, Lee CK, Bertagnolli D, Parikshak NN, Smith KA, Sunkin SM, Amaral DG, Geschwind DH, Lein ES

Abstract
Developmental changes in the temporal and spatial regulation of gene expression drive the emergence of normal mature brain function, while disruptions in these processes underlie many neurodevelopmental abnormalities. To solidify our foundational knowledge of such changes in a primate brain with an extended period of postnatal maturation like in human, we investigated the whole-genome transcriptional profiles of rhesus monkey brains from birth to adulthood. We found that gene expression dynamics are largest from birth through infancy, after which gene expression profiles transition to a relatively stable state by young adulthood. Biological pathway enrichment analysis revealed that genes more highly expressed at birth are associated with cell adhesion and neuron differentiation, while genes more highly expressed in juveniles and adults are associated with cell death. Neocortex showed significantly greater differential expression over time than sub-cortical structures, and this trend likely reflects the protracted postnatal development of the cortex. Using network analysis, we identified 27 co-expression modules containing genes with highly correlated expression patterns that are associated with specific brain regions, ages, or both. In particular, one module with high expression in neonatal cortex and striatum that decreases during infancy and juvenile development was significantly enriched for autism spectrum disorder (ASD)-related genes. This network was enriched for genes associated with axon guidance and interneuron differentiation, consistent with a disruption in the formation of functional cortical circuitry in ASD.

PMID: 25954031 [PubMed - as supplied by publisher]

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