Epigenomic strategies at the interface of genetic and environmental risk factors for autism.

J Hum Genet. 2013 May 16;

Authors: Lasalle JM

Abstract
Autism spectrum disorders (ASD) have been increasing in prevalence over the last two decades, primarily because of increased awareness and diagnosis. However, autism is clearly a complex human genetic disorder that involves interactions between genes and environment. Epigenetic mechanisms, such as DNA methylation, act at the interface of genetic and environmental risk and protective factors. Advancements in genome-wide sequencing has broadened the view of the human methylome and revealed the organization of the human genome into large-scale methylation domains that footprint over neurologically important genes involved in embryonic development. Future integrative epigenomic analyses of genetic risk factors with environmental exposures and methylome analyses are expected to be important for understanding the complex etiology of ASD.Journal of Human Genetics advance online publication, 16 May 2013; doi:10.1038/jhg.2013.49.

PMID: 23677056 [PubMed - as supplied by publisher]

Deletion of Rictor in neural progenitor cells reveals contributions of mTORC2 signaling to tuberous sclerosis complex.

Hum Mol Genet. 2013 Jan 1;22(1):140-52

Authors: Carson RP, Fu C, Winzenburger P, Ess KC

Abstract
Tuberous sclerosis complex (TSC) is a multisystem genetic disorder with severe neurologic manifestations, including epilepsy, autism, anxiety and attention deficit hyperactivity disorder. TSC is caused by the loss of either the TSC1 or TSC2 genes that normally regulate the mammalian target of rapamycin (mTOR) kinase. mTOR exists within two distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Loss of either TSC gene leads to increased mTORC1 but decreased mTORC2 signaling. As the contribution of decreased mTORC2 signaling to neural development and homeostasis has not been well studied, we generated a conditional knockout (CKO) of Rictor, a key component of mTORC2. mTORC2 signaling is impaired in the brain, whereas mTORC1 signaling is unchanged. Rictor CKO mice have small brains and bodies, normal lifespan and are fertile. Cortical layering is normal, but neurons are smaller than those in control brains. Seizures were not observed, although excessive slow activity was seen on electroencephalography. Rictor CKO mice are hyperactive and have reduced anxiety-like behavior. Finally, there is decreased white matter and increased levels of monoamine neurotransmitters in the cerebral cortex. Loss of mTORC2 signaling in the cortex independent of mTORC1 can disrupt normal brain development and function and may contribute to some of the neurologic manifestations seen in TSC.

PMID: 23049074 [PubMed - indexed for MEDLINE]

Genome-wide DNA hydroxymethylation changes are associated with neurodevelopmental genes in the developing human cerebellum.

Hum Mol Genet. 2012 Dec 15;21(26):5500-10

Authors: Wang T, Pan Q, Lin L, Szulwach KE, Song CX, He C, Wu H, Warren ST, Jin P, Duan R, Li X

Abstract
5-Hydroxymethylcytosine (5-hmC) is a newly discovered modified form of cytosine that has been suspected to be an important epigenetic modification in neurodevelopment. While DNA methylation dynamics have already been implicated during neurodevelopment, little is known about hydroxymethylation in this process. Here, we report DNA hydroxymethylation dynamics during cerebellum development in the human brain. Overall, we find a positive correlation between 5-hmC levels and cerebellum development. Genome-wide profiling reveals that 5-hmC is highly enriched on specific gene regions including exons and especially the untranslated regions (UTRs), but it is depleted on introns and intergenic regions. Furthermore, we have identified fetus-specific and adult-specific differentially hydroxymethylated regions (DhMRs), most of which overlap with genes and CpG island shores. Surprisingly, during development, DhMRs are highly enriched in genes encoding mRNAs that can be regulated by fragile X mental retardation protein (FMRP), some of which are disrupted in autism, as well as in many known autism genes. Our results suggest that 5-hmC-mediated epigenetic regulation may broadly impact the development of the human brain, and its dysregulation could contribute to the molecular pathogenesis of neurodevelopmental disorders. Accession number: Sequencing data have been deposited to GEO with accession number GSE40539.

PMID: 23042784 [PubMed - indexed for MEDLINE]

Female Mecp2(+/-) mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies.

Hum Mol Genet. 2013 Jan 1;22(1):96-109

Authors: Samaco RC, McGraw CM, Ward CS, Sun Y, Neul JL, Zoghbi HY

Abstract
Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the gene encoding the transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Typical RTT primarily affects girls and is characterized by a brief period of apparently normal development followed by the loss of purposeful hand skills and language, the onset of anxiety, hand stereotypies, autistic features, seizures and autonomic dysfunction. Mecp2 mouse models have extensively been studied to demonstrate the functional link between MeCP2 dysfunction and RTT pathogenesis. However, the majority of studies have focused primarily on the molecular and behavioral consequences of the complete absence of MeCP2 in male mice. Studies of female Mecp2(+/-) mice have been limited because of potential phenotypic variability due to X chromosome inactivation effects. To determine whether reproducible and reliable phenotypes can be detected Mecp2(+/-) mice, we analyzed Mecp2(+/-) mice of two different F1 hybrid isogenic backgrounds and at young and old ages using several neurobehavioral and physiological assays. Here, we report a multitude of phenotypes in female Mecp2(+/-) mice, some presenting as early as 5 weeks of life. We demonstrate that Mecp2(+/-) mice recapitulate several aspects of typical RTT and show that mosaic expression of MeCP2 does not preclude the use of female mice in behavioral and molecular studies. Importantly, we uncover several behavioral abnormalities that are present in two genetic backgrounds and report on phenotypes that are unique to one background. These findings provide a framework for pre-clinical studies aimed at improving the constellation of phenotypes in a mouse model of RTT.

PMID: 23026749 [PubMed - indexed for MEDLINE]

From Mouse to Human: Evolutionary Genomics Analysis of Human Orthologs of Essential Genes.

PLoS Genet. 2013 May;9(5):e1003484

Authors: Georgi B, Voight BF, Bućan M

Abstract
Understanding the core set of genes that are necessary for basic developmental functions is one of the central goals in biology. Studies in model organisms identified a significant fraction of essential genes through the analysis of null-mutations that lead to lethality. Recent large-scale next-generation sequencing efforts have provided unprecedented data on genetic variation in human. However, evolutionary and genomic characteristics of human essential genes have never been directly studied on a genome-wide scale. Here we use detailed phenotypic resources available for the mouse and deep genomics sequencing data from human populations to characterize patterns of genetic variation and mutational burden in a set of 2,472 human orthologs of known essential genes in the mouse. Consistent with the action of strong, purifying selection, these genes exhibit comparatively reduced levels of sequence variation, skew in allele frequency towards more rare, and exhibit increased conservation across the primate and rodent lineages relative to the remainder of genes in the genome. In individual genomes we observed ∼12 rare mutations within essential genes predicted to be damaging. Consistent with the hypothesis that mutations in essential genes are risk factors for neurodevelopmental disease, we show that de novo variants in patients with Autism Spectrum Disorder are more likely to occur in this collection of genes. While incomplete, our set of human orthologs shows characteristics fully consistent with essential function in human and thus provides a resource to inform and facilitate interpretation of sequence data in studies of human disease.

PMID: 23675308 [PubMed - as supplied by publisher]

Addendum to 'BTBR T+tf/J mice: autism-relevant behaviors and reduced fractone-associated heparan sulfate' [Neurosci. Biobehav. Rev. 36(1) (2012) 285-296].

Neurosci Biobehav Rev. 2012 Nov;36(10):2370

Authors: Blanchard DC, Defensor EB, Meyza KZ, Pobbe RL, Pearson BL, Bolivar VJ, Blanchard RJ

PMID: 23320265 [PubMed - indexed for MEDLINE]

HERVs expression in Autism Spectrum Disorders.

PLoS One. 2012;7(11):e48831

Authors: Balestrieri E, Arpino C, Matteucci C, Sorrentino R, Pica F, Alessandrelli R, Coniglio A, Curatolo P, Rezza G, Macciardi F, Garaci E, Gaudi S, Sinibaldi-Vallebona P

Abstract
BACKGROUND: Autistic Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder, resulting from complex interactions among genetic, genomic and environmental factors. Here we have studied the expression of Human Endogenous Retroviruses (HERVs), non-coding DNA elements with potential regulatory functions, and have tested their possible implication in autism.
METHODS: The presence of retroviral mRNAs from four HERV families (E, H, K and W), widely implicated in complex diseases, was evaluated in peripheral blood mononuclear cells (PBMCs) from ASD patients and healthy controls (HCs) by qualitative RT-PCR. We also analyzed the expression of the env sequence from HERV-H, HERV-W and HERV-K families in PBMCs at the time of sampling and after stimulation in culture, in both ASD and HC groups, by quantitative Real-time PCR. Differences between groups were evaluated using statistical methods.
RESULTS: The percentage of HERV-H and HERV-W positive samples was higher among ASD patients compared to HCs, while HERV-K was similarly represented and HERV-E virtually absent in both groups. The quantitative evaluation shows that HERV-H and HERV-W are differentially expressed in the two groups, with HERV-H being more abundantly expressed and, conversely, HERV-W, having lower abundance, in PBMCs from ASDs compared to healthy controls. PMBCs from ASDs also showed an increased potential to up-regulate HERV-H expression upon stimulation in culture, unlike HCs. Furthermore we report a negative correlation between expression levels of HERV-H and age among ASD patients and a statistically significant higher expression in ASD patients with Severe score in Communication and Motor Psychoeducational Profile-3.
CONCLUSIONS: Specific HERV families have a distinctive expression profile in ASD patients compared to HCs. We propose that HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder.

PMID: 23155411 [PubMed - indexed for MEDLINE]

Potential opposite roles of the extracellular signal-regulated kinase (ERK) pathway in autism spectrum and bipolar disorders.

Neurosci Biobehav Rev. 2012 Nov;36(10):2206-13

Authors: Kalkman HO

Abstract
Signal transduction from the synapse to the nucleus subsequently involves transient increases in synaptic Ca2+, activation of CaM kinases, activation of the GTPase Ras, activation of the ERK mitogen-activated protein kinase pathway, and finally GSK3 inhibition and CREB-activation. Genetic studies in autism have identified mutations and copy number variations in a number of genes involved in this synapse to nucleus signaling path. In particular, a gain of function mutation in the CACNA1C gene, deletions and disruption of the SYNGAP1 gene, a copy number variation encompassing the MAPK3 gene and a duplication of YWHAE indicate that in a subset of autism patients the ERK cascade is inappropriately activated. Predicted functional consequences of this hyperactivation would be an increase in complexity of the dendritic tree, and via inhibition of GSK3, a delayed circadian phase. The latter effect indeed fits the frequent sleep disturbances observed in autistic patients. Interestingly, the sleep disturbances in bipolar disorder patients are frequently characterized as phase advanced. A selective evaluation of genetic mutations in bipolar patients indicates that the activity of the ERK cascade, at least in a subset of patients, presumably is hypoactive. Thus, with respect to the ERK pathway, autism and bipolar disorder seem each other's counter pole.

PMID: 22884480 [PubMed - indexed for MEDLINE]

De Novo Intragenic Deletion of the Autism Susceptibility Candidate 2 (AUTS2) Gene in a Patient With Developmental Delay: A Case Report and Literature Review.

Am J Med Genet A. 2013 May 6;

Authors: Jolley A, Corbett M, McGregor L, Waters W, Brown S, Nicholl J, Yu S

PMID: 23650183 [PubMed - as supplied by publisher]

Fine-scale linkage mapping reveals a small set of candidate genes influencing honey bee grooming behavior in response to Varroa mites.

PLoS One. 2012;7(11):e47269

Authors: Arechavaleta-Velasco ME, Alcala-Escamilla K, Robles-Rios C, Tsuruda JM, Hunt GJ

Abstract
Populations of honey bees in North America have been experiencing high annual colony mortality for 15-20 years. Many apicultural researchers believe that introduced parasites called Varroa mites (V. destructor) are the most important factor in colony deaths. One important resistance mechanism that limits mite population growth in colonies is the ability of some lines of honey bees to groom mites from their bodies. To search for genes influencing this trait, we used an Illumina Bead Station genotyping array to determine the genotypes of several hundred worker bees at over a thousand single-nucleotide polymorphisms in a family that was apparently segregating for alleles influencing this behavior. Linkage analyses provided a genetic map with 1,313 markers anchored to genome sequence. Genotypes were analyzed for association with grooming behavior, measured as the time that individual bees took to initiate grooming after mites were placed on their thoraces. Quantitative-trait-locus interval mapping identified a single chromosomal region that was significant at the chromosome-wide level (p<0.05) on chromosome 5 with a LOD score of 2.72. The 95% confidence interval for quantitative trait locus location contained only 27 genes (honey bee official gene annotation set 2) including Atlastin, Ataxin and Neurexin-1 (AmNrx1), which have potential neurodevelopmental and behavioral effects. Atlastin and Ataxin homologs are associated with neurological diseases in humans. AmNrx1 codes for a presynaptic protein with many alternatively spliced isoforms. Neurexin-1 influences the growth, maintenance and maturation of synapses in the brain, as well as the type of receptors most prominent within synapses. Neurexin-1 has also been associated with autism spectrum disorder and schizophrenia in humans, and self-grooming behavior in mice.

PMID: 23133594 [PubMed - indexed for MEDLINE]

Neurodevelopmental model of schizophrenia: update 2012.

Mol Psychiatry. 2012 Dec;17(12):1228-38

Authors: Rapoport JL, Giedd JN, Gogtay N

Abstract
The neurodevelopmental model of schizophrenia, which posits that the illness is the end state of abnormal neurodevelopmental processes that started years before the illness onset, is widely accepted, and has long been dominant for childhood-onset neuropsychiatric disorders. This selective review updates our 2005 review of recent studies that have impacted, or have the greatest potential to modify or extend, the neurodevelopmental model of schizophrenia. Longitudinal whole-population studies support a dimensional, rather than categorical, concept of psychosis. New studies suggest that placental pathology could be a key measure in future prenatal high-risk studies. Both common and rare genetic variants have proved surprisingly diagnostically nonspecific, and copy number variants (CNVs) associated with schizophrenia are often also associated with autism, epilepsy and intellectual deficiency. Large post-mortem gene expression studies and prospective developmental multi-modal brain imaging studies are providing critical data for future clinical and high-risk developmental brain studies. Whether there can be greater molecular specificity for phenotypic characterization is a subject of current intense study and debate, as is the possibility of neuronal phenotyping using human pluripotent-inducible stem cells. Biological nonspecificity, such as in timing or nature of early brain development, carries the possibility of new targets for broad preventive treatments.

PMID: 22488257 [PubMed - indexed for MEDLINE]

Modeling psychiatric disorders at the cellular and network levels.

Mol Psychiatry. 2012 Dec;17(12):1239-53

Authors: Brennand KJ, Simone A, Tran N, Gage FH

Abstract
Although psychiatric disorders such as autism spectrum disorders, schizophrenia and bipolar disorder affect a number of brain regions and produce a complex array of clinical symptoms, basic phenotypes likely exist at the level of single neurons and simple networks. Being highly heritable, it is hypothesized that these disorders are amenable to cell-based studies in vitro. Using induced pluripotent stem cell-derived neurons and/or induced neurons from fibroblasts, limitless numbers of live human neurons can now be generated from patients with a genetic background permissive to the disease state. We predict that cell-based studies will ultimately contribute to our understanding of the initiation, progression and treatment of these psychiatric disorders.

PMID: 22472874 [PubMed - indexed for MEDLINE]

Family based association of GRIN2A and GRIN2B with Korean autism spectrum disorders.

Neurosci Lett. 2012 Mar 23;512(2):89-93

Authors: Yoo HJ, Cho IH, Park M, Yang SY, Kim SA

Abstract
N-Methyl-d-aspartate (NMDA) receptor, one of the glutamate receptors, has a role in the regulation of synaptic activity. It functions as an ion channel in the central nervous system and its inappropriate activation has been implicated in several neurological conditions. To test the association between candidate genes related with NMDA receptors and autism spectrum disorders (ASDs), we examined single nucleotide polymorphisms (SNPs) for GRIN2A and GRIN2B by using the family-based association test (FBAT) in 151 Korean trios. There was a statistically significant associations between ASDs and haplotypes in GRIN2B (bi-allelic mode additive model P-value=0.003; FDR P-value=0.012). This study supports a possible role of GRIN2B as a candidate gene for the etiology of ASDs.

PMID: 22326929 [PubMed - indexed for MEDLINE]

Rett syndrome induced pluripotent stem cell-derived neurons reveal novel neurophysiological alterations.

Mol Psychiatry. 2012 Dec;17(12):1261-71

Authors: Farra N, Zhang WB, Pasceri P, Eubanks JH, Salter MW, Ellis J

Abstract
Rett syndrome (RTT) is a neurodevelopmental autism spectrum disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Here, we describe the first characterization and neuronal differentiation of induced pluripotent stem (iPS) cells derived from Mecp2-deficient mice. Fully reprogrammed wild-type (WT) and heterozygous female iPS cells express endogenous pluripotency markers, reactivate the X-chromosome and differentiate into the three germ layers. We directed iPS cells to produce glutamatergic neurons, which generated action potentials and formed functional excitatory synapses. iPS cell-derived neurons from heterozygous Mecp2(308) mice showed defects in the generation of evoked action potentials and glutamatergic synaptic transmission, as previously reported in brain slices. Further, we examined electrophysiology features not yet studied with the RTT iPS cell system and discovered that MeCP2-deficient neurons fired fewer action potentials, and displayed decreased action potential amplitude, diminished peak inward currents and higher input resistance relative to WT iPS-derived neurons. Deficiencies in action potential firing and inward currents suggest that disturbed Na(+) channel function may contribute to the dysfunctional RTT neuronal network. These phenotypes were additionally confirmed in neurons derived from independent WT and hemizygous mutant iPS cell lines, indicating that these reproducible deficits are attributable to MeCP2 deficiency. Taken together, these results demonstrate that neuronally differentiated MeCP2-deficient iPS cells recapitulate deficits observed previously in primary neurons, and these identified phenotypes further illustrate the requirement of MeCP2 in neuronal development and/or in the maintenance of normal function. By validating the use of iPS cells to delineate mechanisms underlying RTT pathogenesis, we identify deficiencies that can be targeted for in vitro translational screens.

PMID: 22230884 [PubMed - indexed for MEDLINE]

Balanced translocation t(3;18)(p13;q22.3) and points mutation in the ZNF407 gene detected in patients with both moderate non-syndromic intellectual disability and autism.

Biochim Biophys Acta. 2013 Mar;1832(3):431-8

Authors: Ren CM, Liang Y, Wei F, Zhang YN, Zhong SQ, Gu H, Dong XS, Huang YY, Ke H, Son XM, Tang D, Chen Z

Abstract
Intellectual disability (ID) is a common disease. While the etiology remains incompletely understood, genetic defects are a major contributor, which include mutations in genes encoding zinc finger proteins. These proteins modulate gene expression via binding to DNA. Consistent with this knowledge, we report here the identification of mutations in the ZNF407 gene in ID/autistic patients. In our study of an ID patient with autism, a reciprocal translocation 46,XY,t(3;18)(p13;q22.3) was detected. By using FISH and long-range PCR approaches, we have precisely mapped the breakpoints associated with this translocation in a gene-free region in chromosome 3 and in the third intron of the ZNF407 gene in chromosome18. The latter reduces ZNF407 expression. Consistent with this observation, in our subsequent investigation of 105 ID/autism patients with similar clinical presentations, two missense mutations Y460C and P1195A were identified. These mutations cause non-conservative amino acid substitutions in the linker regions between individual finger structures. In line with the linker regions being critical for the integrity of zinc finger motifs, both mutations may result in loss of ZNF407 function. Taken together, we demonstrate that mutations in the ZNF407 gene contribute to the pathogenesis of a group of ID patients with autism.

PMID: 23195952 [PubMed - indexed for MEDLINE]

Pitt-Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription.

Exp Mol Med. 2013;45:e21

Authors: Sweatt JD

Abstract
TCF4 (transcription factor 4; E2-2, ITF2) is a transcription factor that when haplo-insufficient causes Pitt-Hopkins Syndrome (PTHS), an autism-spectrum disorder that is associated with pervasive developmental delay and severe intellectual disability. The TCF4 gene is also a risk factor with highly significant linkage to schizophrenia, presumably via overexpression of the TCF4 gene product in the central nervous system. This review will present an overview of the clinical manifestations of PTHS and relate those clinical attributes to the underlying molecular genetics of TCF4. In order to provide a molecular biological context for the loss of function of TCF4 in PTHS, the review will also present a brief overview of the basic biochemistry of TCF4-mediated regulation of cellular and neuronal gene expression. In the final section of this review, I will discuss and speculate upon possible roles for the TCF4 transcription factor in neuronal function and comment upon how understanding these roles may give new insights into the molecular neurobiology of human cognition.

PMID: 23640545 [PubMed - in process]

Autism and the broad autism phenotype: familial patterns and intergenerational transmission.

J Neurodev Disord. 2013 May 2;5(1):11

Authors: Sasson NJ, Lam KS, Parlier M, Daniels JL, Piven J

Abstract
BACKGROUND: Features of the Broad Autism Phenotype (BAP) are disproportionately prevalent in parents of a child with autism, highlighting familial patterns indicative of heritability. It is unclear, however, whether the presence of BAP features in both parents confers an increased liability for autism. The current study explores whether the presence of BAP features in two biological parents occurs more frequently in parents of a child with autism relative to comparison parents, whether parental pairs of a child with autism more commonly consist of one or two parents with BAP features, and whether these features are associated with severity of autism behaviors in probands. METHOD: Seven hundred eleven parents of a child with an autism spectrum disorder and 981 comparison parents completed the Broad Autism Phenotype Questionnaire. Parents of a child with autism also completed the Social Communication Questionnaire. RESULTS: Although parental pairs of a child with autism were more likely than comparison parental pairs to have both parents characterized by the presence of the BAP, they more commonly consisted of a single parent with BAP features. The presence of the BAP in parents was associated with the severity of autism behaviors in probands, with the lowest severity occurring for children of parental pairs in which neither parent exhibited a BAP feature. Severity did not differ between children of two affected parents and those of just one. CONCLUSIONS: Collectively, these findings indicate that parental pairs of children with autism frequently consist of a single parent with BAP characteristics and suggest that future studies searching for implicated genes may benefit from a more narrow focus that identifies the transmitting parent. The evidence of intergenerational transmission reported here also provides further confirmation of the high heritability of autism that is unaccounted for by the contribution of de novo mutations currently emphasized in the field of autism genetics.

PMID: 23639131 [PubMed - as supplied by publisher]

Human alpha- and beta-NRXN1 isoforms rescue behavioral impairments of C. elegans neurexin-deficient mutants.

Genes Brain Behav. 2013 May 2;

Authors: Calahorro F, Ruiz-Rubio M

Abstract
Neurexins are cell adhesion proteins that interact with neuroligin and other ligands at the synapse. In humans, mutations in neurexin or neuroligin genes have been associated with autism and other mental disorders. The human neurexin and neuroligin genes are orthologous to the C. elegans genes nrx-1 and nlg-1, respectively. Here we show that nrx-1-deficient mutants are defective in exploratory capacity, sinusoidal postural movements and gentle touch response. Interestingly, the exploratory behavioral phenotype observed in nrx-1 mutants was markedly different to nlg-1-deficient mutants; thus, while the former had a "hyper-reversal" phenotype increasing the number of changes of direction with respect to the wild type strain, the nlg-1 mutants presented a "hypo-reversal" phenotype. On the other hand, the nrx-1- and nlg-1-defective mutants showed similar abnormal sinusoidal postural movement phenotypes. The response of these mutant strains to aldicarb (acetylcholinesterase inhibitor), levamisole (ACh agonist) and pentylenetetrazole (GABA receptor antagonist), suggested that the varying behavioral phenotypes were caused by defects in ACh and/or GABA inputs. The defective behavioral phenotypes of nrx-1-deficient mutants were rescued in transgenic strains expressing either human alpha- or beta-NRXN-1 isoforms under the worm nrx-1 promoter. A previous report had shown that human and rat neuroligins were functional in C. elegans. Together, these results suggest that the functional mechanism underpinning both neuroligin and neurexin in the nematode are comparable to human. In this sense the nematode might constitute a simple in vivo model for understanding basic mechanisms involved in neurological diseases for which neuroligin and neurexin are implicated in having a role.

PMID: 23638761 [PubMed - as supplied by publisher]

A simple cell-based assay reveals that diverse neuropsychiatric risk genes converge on primary cilia.

PLoS One. 2012;7(10):e46647

Authors: Marley A, von Zastrow M

Abstract
Human genetic studies are beginning to identify a large number of genes linked to neuropsychiatric disorders. It is increasingly evident that different genes contribute to risk for similar syndromes and, conversely, the same genes or even the same alleles cross over traditional diagnostic categories. A current challenge is to understand the cellular biology of identified risk genes. However, most genes associated with complex neuropsychiatric phenotypes are not related through a known biochemical pathway, and many have an entirely unknown cellular function. One possibility is that diverse disease-linked genes converge at a higher-level cellular structure. The synapse is already known to be one such convergence, and emerging evidence suggests the primary cilium as another. Because many genes associated with neuropsychiatric illness are expressed also outside the nervous system, as are cilia, we tested the hypothesis that such genes affect conserved features of the primary cilium. Using RNA interference to test 41 broadly expressed candidate genes associated with schizophrenia, bipolar affective disorder, autism spectrum disorder and intellectual disability, we found 20 candidates that reduce ciliation in NIH3T3 cells when knocked down, and three whose manipulation increases cilia length. Three of the candidate genes were previously implicated in cilia formation and, altogether, approximately half of the candidates tested produced a ciliary phenotype. Our results support the hypothesis that primary cilia indeed represent a conserved cellular structure at which the effects of diverse neuropsychiatric risk genes converge. More broadly, they suggest a relatively simple cell-based approach that may be useful for exploring the complex biological underpinnings of neuropsychiatric disease.

PMID: 23056384 [PubMed - indexed for MEDLINE]

Mitochondrial and ion channel gene alterations in autism.

Biochim Biophys Acta. 2012 Oct;1817(10):1796-802

Authors: Smith M, Flodman PL, Gargus JJ, Simon MT, Verrell K, Haas R, Reiner GE, Naviaux R, Osann K, Spence MA, Wallace DC

Abstract
To evaluate the potential importance in autistic subjects of copy number variants (CNVs) that alter genes of relevance to bioenergetics, ionic metabolism, and synaptic function, we conducted a detailed microarray analysis of 69 autism probands and 35 parents, compared to 89 CEU HapMap controls. This revealed that the frequency CNVs of≥100kb and CNVs of≥10 Kb were markedly increased in probands over parents and in probands and parents over controls. Evaluation of CNVs≥1Mb by chromosomal FISH confirmed the molecular identity of a subset of the CNVs, some of which were associated with chromosomal rearrangements. In a number of the cases, CNVs were found to alter the copy number of genes that are important in mitochondrial oxidative phosphorylation (OXPHOS), ion and especially calcium transport, and synaptic structure. Hence, autism might result from alterations in multiple bioenergetic and metabolic genes required for mental function. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).

PMID: 22538295 [PubMed - indexed for MEDLINE]