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[Application of whole exome sequencing in the diagnosis of hereditary neurological diseases].

April 25, 2015 - 6:46am

[Application of whole exome sequencing in the diagnosis of hereditary neurological diseases].

Zh Nevrol Psikhiatr Im S S Korsakova. 2015;115(1):45-52

Authors: Il'inskiĭ VV, Korneeva VA, Shatalov PA

Abstract
Whole Exome Sequencing (WES) is a promising method in human genetics. Because the majority of pathogenic mutations that lead to the development of diseases are localized in exons and splice sites, WES could become a major tool for the diagnosis of diseases with a complex hereditary nature. This tool appears to be particularly useful for hereditary neurological diseases, such as autism spectrum disorders, Charcot-Marie-Tooth disease and others. In our review, we discuss the clinical application of WES, with special emphasis on the diagnosis of hereditary neurological diseases.

PMID: 25909789 [PubMed - as supplied by publisher]

Genetic investigation of autism-related social communication deficits.

April 25, 2015 - 6:46am
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Genetic investigation of autism-related social communication deficits.

Am J Psychiatry. 2015 Mar 1;172(3):212-3

Authors: Campbell DB

PMID: 25727530 [PubMed - indexed for MEDLINE]

Clinical and molecular delineation of duplication 9p24.3q21.11 in a patient with psychotic behavior.

April 25, 2015 - 6:46am
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Clinical and molecular delineation of duplication 9p24.3q21.11 in a patient with psychotic behavior.

Gene. 2015 Apr 10;560(1):124-7

Authors: Martínez-Jacobo L, Ortíz-López R, Rizo-Méndez A, García-Molina V, Santuario-Facio SK, Rivas F, Rojas-Martínez A

Abstract
This article describes a 19-year-old female with mild facial dysmorphism, asociality, decreased school performance, and psychotic behavior in whom the karyotype showed an extra-chromosomal marker characterized as 9p24.3-9q21.11 duplication by array-CGH. The 69Mbp duplicated segment in this patient includes the critical 9p duplication syndrome region, the GLDC and C90RF72 genes associated with psychotic behavior and other conduct disorders, and a potential locus for autism.

PMID: 25667990 [PubMed - indexed for MEDLINE]

CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.

April 25, 2015 - 6:46am
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CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.

Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4468-77

Authors: Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I, Manavalan P, Ragavendran A, Brand H, Lucente D, Miles J, Sheridan SD, Stortchevoi A, Kellis M, Haggarty SJ, Katsanis N, Gusella JF, Talkowski ME

Abstract
Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10(-8)) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10(-10)). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis.

PMID: 25294932 [PubMed - indexed for MEDLINE]

Autism as a disorder of prediction.

April 25, 2015 - 6:46am
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Autism as a disorder of prediction.

Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15220-5

Authors: Sinha P, Kjelgaard MM, Gandhi TK, Tsourides K, Cardinaux AL, Pantazis D, Diamond SP, Held RM

Abstract
A rich collection of empirical findings accumulated over the past three decades attests to the diversity of traits that constitute the autism phenotypes. It is unclear whether subsets of these traits share any underlying causality. This lack of a cohesive conceptualization of the disorder has complicated the search for broadly effective therapies, diagnostic markers, and neural/genetic correlates. In this paper, we describe how theoretical considerations and a review of empirical data lead to the hypothesis that some salient aspects of the autism phenotype may be manifestations of an underlying impairment in predictive abilities. With compromised prediction skills, an individual with autism inhabits a seemingly "magical" world wherein events occur unexpectedly and without cause. Immersion in such a capricious environment can prove overwhelming and compromise one's ability to effectively interact with it. If validated, this hypothesis has the potential of providing unifying insights into multiple aspects of autism, with attendant benefits for improving diagnosis and therapy.

PMID: 25288765 [PubMed - indexed for MEDLINE]

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences.

April 25, 2015 - 6:46am
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Autism spectrum disorder severity reflects the average contribution of de novo and familial influences.

Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15161-5

Authors: Robinson EB, Samocha KE, Kosmicki JA, McGrath L, Neale BM, Perlis RH, Daly MJ

Abstract
Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions--phenotypically and genetically--although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.

PMID: 25288738 [PubMed - indexed for MEDLINE]

No association of the norepinephrine transporter gene (SLC6A2) and cognitive and behavioural phenotypes of patients with autism spectrum disorder.

April 24, 2015 - 11:52am
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No association of the norepinephrine transporter gene (SLC6A2) and cognitive and behavioural phenotypes of patients with autism spectrum disorder.

Eur Arch Psychiatry Clin Neurosci. 2014 Sep;264(6):507-15

Authors: Park S, Park JE, Cho SC, Kim BN, Shin MS, Kim JW, Cho IH, Kim SA, Park M, Park TW, Son JW, Chung US, Yoo HJ

Abstract
We examined the association between the norepinephrine transporter (SLC6A2) gene and autism spectrum disorder (ASD) in a Korean population. In addition, we investigated which phenotypes of ASD are best attributed to the genotype of SLC6A2. A total of 184 subjects with ASD, their 156 unaffected siblings and both biological parents were recruited through university hospitals. We used the Autism Diagnostic Interview-Revised, the Aberrant Behaviour Checklist (ABC), the Child Behaviour Checklist (CBCL), the Stroop Colour-Word Interference Test and the Wisconsin Card Sorting Test (WCST) as quantitative measures of the ASD phenotypes. The associations between the quantitative measures and specific single-nucleotide polymorphisms (SNPs) were tested with linear regression analyses. We did not find any evidence of the over-transmission of either allele of the 10SLC6A2 SNPs in the DFAM test. At an empirical p value <0.05, findings that were consistent between the linear regression analyses and the QFAM tests were the positive associations between the A allele of rs36020 and attention problems on the CBCL and stereotypical behaviours on the ABC and between the C allele of rs1814270 and the number of trials required to complete the first WCST category. However, these associations did not remain after correction for multiple testing. The study results of this study do not support the association between the SLC6A2 and the diagnosis or phenotype of ASD. However, the study must be replicated in larger populations and with using more genetic markers.

PMID: 24381062 [PubMed - indexed for MEDLINE]

Autism and Intellectual Disability-Associated KIRREL3 Interacts with Neuronal Proteins MAP1B and MYO16 with Potential Roles in Neurodevelopment.

April 23, 2015 - 7:09am

Autism and Intellectual Disability-Associated KIRREL3 Interacts with Neuronal Proteins MAP1B and MYO16 with Potential Roles in Neurodevelopment.

PLoS One. 2015;10(4):e0123106

Authors: Liu YF, Sowell SM, Luo Y, Chaubey A, Cameron RS, Kim HG, Srivastava AK

Abstract
Cell-adhesion molecules of the immunoglobulin superfamily play critical roles in brain development, as well as in maintaining synaptic plasticity, the dysfunction of which is known to cause cognitive impairment. Recently dysfunction of KIRREL3, a synaptic molecule of the immunoglobulin superfamily, has been implicated in several neurodevelopmental conditions including intellectual disability, autism spectrum disorder, and in the neurocognitive delay associated with Jacobsen syndrome. However, the molecular mechanisms of its physiological actions remain largely unknown. Using a yeast two-hybrid screen, we found that the KIRREL3 extracellular domain interacts with brain expressed proteins MAP1B and MYO16 and its intracellular domain can potentially interact with ATP1B1, UFC1, and SHMT2. The interactions were confirmed by co-immunoprecipitation and colocalization analyses of proteins expressed in human embryonic kidney cells, mouse neuronal cells, and rat primary neuronal cells. Furthermore, we show KIRREL3 colocalization with the marker for the Golgi apparatus and synaptic vesicles. Previously, we have shown that KIRREL3 interacts with the X-linked intellectual disability associated synaptic scaffolding protein CASK through its cytoplasmic domain. In addition, we found a genomic deletion encompassing MAP1B in one patient with intellectual disability, microcephaly and seizures and deletions encompassing MYO16 in two unrelated patients with intellectual disability, autism and microcephaly. MAP1B has been previously implicated in synaptogenesis and is involved in the development of the actin-based membrane skeleton. MYO16 is expressed in hippocampal neurons and also indirectly affects actin cytoskeleton through its interaction with WAVE1 complex. We speculate KIRREL3 interacting proteins are potential candidates for intellectual disability and autism spectrum disorder. Moreover, our findings provide further insight into understanding the molecular mechanisms underlying the physiological action of KIRREL3 and its role in neurodevelopment.

PMID: 25902260 [PubMed - as supplied by publisher]

Homozygosity analysis in subjects with autistic spectrum disorder.

April 23, 2015 - 7:09am

Homozygosity analysis in subjects with autistic spectrum disorder.

Mol Med Rep. 2015 Apr 22;

Authors: Adi A, Tawil B, Aldosari M, Shinwari J, Nester M, Aldhalaan H, Alshamrani H, Ghannam M, Meyer B, Al Tassan N

Abstract
Autistic spectrum disorder (ASD) is a complex neurodevelopmental disorder that results in social and communication impairments, as well as repetitive and stereotyped patterns. Genetically, ASD has been described as a multifactorial genetic disorder. The aim of the present study was to investigate possible susceptibility loci of ASD, utilizing the highly consanguineous and inbred nature of numerous families within the population of Saudi Arabia. A total of 13 multiplex families and 27 affected individuals were recruited and analyzed using Affymetrix GeneChip® Mapping 250K and 6.0 arrays as well as Axiom arrays. Numerous regions of homozygosity were identified, including regions in genes associated with synaptic function and neurotransmitters, as well as energy and mitochondria‑associated genes, and developmentally‑associated genes. The loci identified in the present study represent regions that may be further investigated, which could reveal novel changes and variations associated with ASD, reinforcing the complex inheritance of the disease.

PMID: 25901489 [PubMed - as supplied by publisher]

Autism spectrum disorder and epilepsy: Disorders with a shared biology.

April 23, 2015 - 7:09am

Autism spectrum disorder and epilepsy: Disorders with a shared biology.

Epilepsy Behav. 2015 Apr 18;

Authors: Lee BH, Smith T, Paciorkowski AR

Abstract
There is an increasing recognition of clinical overlap in patients presenting with epilepsy and autism spectrum disorder (ASD), and a great deal of new information regarding the genetic causes of both disorders is available. Several biological pathways appear to be involved in both disease processes, including gene transcription regulation, cellular growth, synaptic channel function, and maintenance of synaptic structure. We review several genetic disorders where ASD and epilepsy frequently co-occur, and we discuss the screening tools available for practicing neurologists and epileptologists to help determine which patients should be referred for formal ASD diagnostic evaluation. Finally, we make recommendations regarding the workflow of genetic diagnostic testing available for children with both ASD and epilepsy. This article is part of a Special Issue entitled "Autism and Epilepsy".

PMID: 25900226 [PubMed - as supplied by publisher]

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism.

April 23, 2015 - 7:09am

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism.

Eur J Hum Genet. 2015 Apr 22;

Authors: Machado CO, Griesi-Oliveira K, Rosenberg C, Kok F, Martins S, Rita Passos-Bueno M, Sertie AL

Abstract
Protein synthesis regulation via mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has key roles in neural development and function, and its dysregulation is involved in neurodevelopmental disorders associated with autism and intellectual disability. mTOR regulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3 complex and by controlling phosphorylation of key translational regulators. Collybistin (CB), a neuron-specific Rho-GEF responsible for X-linked intellectual disability with epilepsy, also interacts with eIF3, and its binding partner gephyrin associates with mTOR. Therefore, we hypothesized that CB also binds mTOR and affects mTORC1 signaling activity in neuronal cells. Here, by using induced pluripotent stem cell-derived neural progenitor cells from a male patient with a deletion of entire CB gene and from control individuals, as well as a heterologous expression system, we describe that CB physically interacts with mTOR and inhibits mTORC1 signaling pathway and protein synthesis. These findings suggest that disinhibited mTORC1 signaling may also contribute to the pathological process in patients with loss-of-function variants in CB.European Journal of Human Genetics advance online publication, 22 April 2015; doi:10.1038/ejhg.2015.69.

PMID: 25898924 [PubMed - as supplied by publisher]

Conformational stability and catalytic activity of PTEN variants linked to cancers and autism spectrum disorders.

April 23, 2015 - 7:09am
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Conformational stability and catalytic activity of PTEN variants linked to cancers and autism spectrum disorders.

Biochemistry. 2015 Feb 24;54(7):1576-82

Authors: Johnston SB, Raines RT

Abstract
Phosphoinositides are membrane components that play critical regulatory roles in mammalian cells. The enzyme PTEN, which catalyzes the dephosphorylation of the phosphoinositide PIP3, is damaged in most sporadic tumors. Mutations in the PTEN gene have also been linked to autism spectrum disorders and other forms of delayed development. Here, human PTEN is shown to be on the cusp of unfolding under physiological conditions. Variants of human PTEN linked to somatic cancers and disorders on the autism spectrum are shown to be impaired in their conformational stability, catalytic activity, or both. Those variants linked only to autism have activity higher than the activity of those linked to cancers. PTEN-L, which is a secreted trans-active isoform, has conformational stability greater than that of the wild-type enzyme. These data indicate that PTEN is a fragile enzyme cast in a crucial role in cellular metabolism and suggest that PTEN-L is a repository for a critical catalytic activity.

PMID: 25647146 [PubMed - indexed for MEDLINE]

Maturation of cortical circuits requires Semaphorin 7A.

April 23, 2015 - 7:09am
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Maturation of cortical circuits requires Semaphorin 7A.

Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):13978-83

Authors: Carcea I, Patil SB, Robison AJ, Mesias R, Huntsman MM, Froemke RC, Buxbaum JD, Huntley GW, Benson DL

Abstract
Abnormal cortical circuits underlie some cognitive and psychiatric disorders, yet the molecular signals that generate normal cortical networks remain poorly understood. Semaphorin 7A (Sema7A) is an atypical member of the semaphorin family that is GPI-linked, expressed principally postnatally, and enriched in sensory cortex. Significantly, SEMA7A is deleted in individuals with 15q24 microdeletion syndrome, characterized by developmental delay, autism, and sensory perceptual deficits. We studied the role that Sema7A plays in establishing functional cortical circuitry in mouse somatosensory barrel cortex. We found that Sema7A is expressed in spiny stellate cells and GABAergic interneurons and that its absence disrupts barrel cytoarchitecture, reduces asymmetrical orientation of spiny stellate cell dendrites, and functionally impairs thalamocortically evoked synaptic responses, with reduced feed-forward GABAergic inhibition. These data identify Sema7A as a regulator of thalamocortical and local circuit development in layer 4 and provide a molecular handle that can be used to explore the coordinated generation of excitatory and inhibitory cortical circuits.

PMID: 25201975 [PubMed - indexed for MEDLINE]

Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming.

April 23, 2015 - 7:09am
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Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming.

Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):E4033-42

Authors: Picard M, Zhang J, Hancock S, Derbeneva O, Golhar R, Golik P, O'Hearn S, Levy S, Potluri P, Lvova M, Davila A, Lin CS, Perin JC, Rappaport EF, Hakonarson H, Trounce IA, Procaccio V, Wallace DC

Abstract
Variation in the intracellular percentage of normal and mutant mitochondrial DNAs (mtDNA) (heteroplasmy) can be associated with phenotypic heterogeneity in mtDNA diseases. Individuals that inherit the common disease-causing mtDNA tRNA(Leu(UUR)) 3243A>G mutation and harbor ∼10-30% 3243G mutant mtDNAs manifest diabetes and occasionally autism; individuals with ∼50-90% mutant mtDNAs manifest encephalomyopathies; and individuals with ∼90-100% mutant mtDNAs face perinatal lethality. To determine the basis of these abrupt phenotypic changes, we generated somatic cell cybrids harboring increasing levels of the 3243G mutant and analyzed the associated cellular phenotypes and nuclear DNA (nDNA) and mtDNA transcriptional profiles by RNA sequencing. Small increases in mutant mtDNAs caused relatively modest defects in oxidative capacity but resulted in sharp transitions in cellular phenotype and gene expression. Cybrids harboring 20-30% 3243G mtDNAs had reduced mtDNA mRNA levels, rounded mitochondria, and small cell size. Cybrids with 50-90% 3243G mtDNAs manifest induction of glycolytic genes, mitochondrial elongation, increased mtDNA mRNA levels, and alterations in expression of signal transduction, epigenomic regulatory, and neurodegenerative disease-associated genes. Finally, cybrids with 100% 3243G experienced reduced mtDNA transcripts, rounded mitochondria, and concomitant changes in nuclear gene expression. Thus, striking phase changes occurred in nDNA and mtDNA gene expression in response to the modest changes of the mtDNA 3243G mutant levels. Hence, a major factor in the phenotypic variation in heteroplasmic mtDNA mutations is the limited number of states that the nucleus can acquire in response to progressive changes in mitochondrial retrograde signaling.

PMID: 25192935 [PubMed - indexed for MEDLINE]

Microphthalmia with Linear Skin Defects (MLS) associated with Autism Spectrum Disorder (ASD) in a patient with Familial 12.9Mb Terminal Xp deletion.

April 18, 2015 - 7:15am
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Microphthalmia with Linear Skin Defects (MLS) associated with Autism Spectrum Disorder (ASD) in a patient with Familial 12.9Mb Terminal Xp deletion.

BMC Pediatr. 2014;14:220

Authors: Margari L, Colonna A, Craig F, Gentile M, Giannella G, Lamanna AL, Legrottaglie AR

Abstract
BACKGROUND: Microphthalmia with linear skin defects (MLS) syndrome is a rare X-linked dominant male-lethal developmental disorder characterized by unilateral or bilateral microphthalmia and linear skin defects of the face and neck. Additional features affecting the eyes, heart, brain or genitourinary system can occur, corroborating the intra- and interfamilial phenotypic variability. The majority of patients display monosomy of the Xp22.2 region, where the holocytochrome c-type synthase (HCCS) gene is located.
CASE PRESENTATION: We describe a 15-year-old-female affected by MLS syndrome and autism spectrum disorder (ASD). ASD has not previously been reported as a component of MLS. Our patient shows a large deletion of 12.9 Mb, involving Xp22.32-p22.2, which encompasses both the HCCS gene and autism X-linked genes.
CONCLUSION: Thus, patients with a large deletion at Xp22 might display MLS with ASD, due to the deletion of contiguous genes, although the highly variable phenotype of these patients could be influenced by several genetic mechanisms, including different tissue-specific X-inactivation and somatic mosaicism.

PMID: 25182979 [PubMed - indexed for MEDLINE]

Disease genomics: autism sibling differences.

April 17, 2015 - 6:09am
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Disease genomics: autism sibling differences.

Nat Rev Genet. 2015 Mar;16(3):130

Authors: Jones B

PMID: 25668784 [PubMed - indexed for MEDLINE]

Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.

April 16, 2015 - 7:39am
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Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.

Mol Psychiatry. 2014 Jul;19(7):784-90

Authors: Toma C, Torrico B, Hervás A, Valdés-Mas R, Tristán-Noguero A, Padillo V, Maristany M, Salgado M, Arenas C, Puente XS, Bayés M, Cormand B

Abstract
Autism is a severe neurodevelopmental disorder, the aetiology of which remains mainly unknown. Family and twin studies provide strong evidence that genetic factors have a major role in the aetiology of this disease. Recently, whole exome sequencing (WES) efforts have focused mainly on rare de novo variants in singleton families. Although these studies have provided pioneering insights, de novo variants probably explain only a small proportion of the autism risk variance. In this study, we performed exome sequencing of 10 autism multiplex families with the aim of investigating the role of rare variants that are coinherited in the affected sibs. The pool of variants selected in our study is enriched with genes involved in neuronal functions or previously reported in psychiatric disorders, as shown by Gene Ontology analysis and by browsing the Neurocarta database. Our data suggest that rare truncating heterozygous variants have a predominant role in the aetiology of autism. Using a multiple linear regression model, we found that the burden of truncating mutations correlates with a lower non-verbal intelligence quotient (NVIQ). Also, the number of truncating mutations that were transmitted to the affected sibs was significantly higher (twofold) than those not transmitted. Protein-protein interaction analysis performed with our list of mutated genes revealed that the postsynaptic YWHAZ is the most interconnected node of the network. Among the genes found disrupted in our study, there is evidence suggesting that YWHAZ and also the X-linked DRP2 may be considered as novel autism candidate genes.

PMID: 23999528 [PubMed - indexed for MEDLINE]

Identification of differentially expressed microRNAs across the developing human brain.

April 16, 2015 - 7:39am
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Identification of differentially expressed microRNAs across the developing human brain.

Mol Psychiatry. 2014 Jul;19(7):848-52

Authors: Ziats MN, Rennert OM

Abstract
We present a spatio-temporal assessment of microRNA (miRNA) expression throughout early human brain development. We assessed the prefrontal cortex, hippocampus and cerebellum of 18 normal human donor brains spanning infancy through adolescence by RNA-seq. We discovered differentially expressed miRNAs and broad miRNA patterns across both temporal and spatial dimensions, and between male and female prefrontal cortex. Putative target genes of the differentially expressed miRNAs were identified, which demonstrated functional enrichment for transcription regulation, synaptogenesis and other basic intracellular processes. Sex-biased miRNAs also targeted genes related to Wnt and transforming growth factor-beta pathways. The differentially expressed miRNA targets were highly enriched for gene sets related to autism, schizophrenia, bipolar disorder and depression, but not neurodegenerative diseases, epilepsy or other adult-onset psychiatric diseases. Our results suggest critical roles for the identified miRNAs in transcriptional networks of the developing human brain and neurodevelopmental disorders.

PMID: 23917947 [PubMed - indexed for MEDLINE]

NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse.

April 15, 2015 - 6:06am

NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse.

Mol Psychiatry. 2015 Apr 14;

Authors: Schuster S, Rivalan M, Strauss U, Stoenica L, Trimbuch T, Rademacher N, Parthasarathy S, Lajkó D, Rosenmund C, Shoichet SA, Winter Y, Tarabykin V, Rosário M

Abstract
Neuropsychiatric developmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia, are typically characterized by alterations in social behavior and have been linked to aberrant dendritic spine and synapse development. Here we show, using genetically engineered mice, that the Cdc42 GTPase-activating multiadaptor protein, NOMA-GAP, regulates autism-like social behavior in the mouse, as well as dendritic spine and synapse development. Surprisingly, we were unable to restore spine morphology or autism-associated social behavior in NOMA-GAP-deficient animals by Cre-mediated deletion of Cdc42 alone. Spine morphology can be restored in vivo by re-expression of wild-type NOMA-GAP or a mutant of NOMA-GAP that lacks the RhoGAP domain, suggesting that other signaling functions are involved. Indeed, we show that NOMA-GAP directly interacts with several MAGUK (membrane-associated guanylate kinase) proteins, and that this modulates NOMA-GAP activity toward Cdc42. Moreover, we demonstrate that NOMA-GAP is a major regulator of PSD-95 in the neocortex. Loss of NOMA-GAP leads to strong upregulation of serine 295 phosphorylation of PSD-95 and moreover to its subcellular mislocalization. This is associated with marked loss of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and defective synaptic transmission, thereby providing a molecular basis for autism-like social behavior in the absence of NOMA-GAP.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.42.

PMID: 25869807 [PubMed - as supplied by publisher]

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.

April 15, 2015 - 6:06am
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The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.

Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):E4779-88

Authors: Mergy MA, Gowrishankar R, Gresch PJ, Gantz SC, Williams J, Davis GL, Wheeler CA, Stanwood GD, Hahn MK, Blakely RD

Abstract
Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPH-evoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.

PMID: 25331903 [PubMed - indexed for MEDLINE]

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