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AMPD1 functional variants associated with autism in Han Chinese population.

June 2, 2016 - 8:19am
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AMPD1 functional variants associated with autism in Han Chinese population.

Eur Arch Psychiatry Clin Neurosci. 2015 Sep;265(6):511-7

Authors: Zhang L, Ou J, Xu X, Peng Y, Guo H, Pan Y, Chen J, Wang T, Peng H, Liu Q, Tian D, Pan Q, Zou X, Zhao J, Hu Z, Xia K

Abstract
Autism is a childhood neurodevelopmental disorder with high heterogeneity. Following our genome-wide associated loci with autism, we performed sequencing analysis of the coding regions, UTR and flanking splice junctions of AMPD1 in 830 Chinese autism individuals as well as 514 unrelated normal controls. Fourteen novel variants in the coding sequence were identified, including 11 missense variants and 3 synonymous mutations. Among these missense variants, 10 variants were absent in 514 control subjects, and conservative and functional prediction was carried out. Mitochondria activity and lactate dehydrogenase assay were performed in 5 patients' lymphoblast cell lines; p.P572S and p.S626C showed decreased mitochondrial complex I activity, and p.S626C increased lactate dehydrogenase release in medium. Conclusively, our data suggested that mutational variants in AMPD1 contribute to autism risk in Han Chinese population, uncovering the contribution of mutant protein to disease development that operates via mitochondria dysfunction and cell necrosis.

PMID: 25155876 [PubMed - indexed for MEDLINE]

Modeling psychiatric disorders: from genomic findings to cellular phenotypes.

June 1, 2016 - 11:10am

Modeling psychiatric disorders: from genomic findings to cellular phenotypes.

Mol Psychiatry. 2016 May 31;

Authors: Falk A, Heine VM, Harwood AJ, Sullivan PF, Peitz M, Brüstle O, Shen S, Sun YM, Glover JC, Posthuma D, Djurovic S

Abstract
Major programs in psychiatric genetics have identified >150 risk loci for psychiatric disorders. These loci converge on a small number of functional pathways, which span conventional diagnostic criteria, suggesting a partly common biology underlying schizophrenia, autism and other psychiatric disorders. Nevertheless, the cellular phenotypes that capture the fundamental features of psychiatric disorders have not yet been determined. Recent advances in genetics and stem cell biology offer new prospects for cell-based modeling of psychiatric disorders. The advent of cell reprogramming and induced pluripotent stem cells (iPSC) provides an opportunity to translate genetic findings into patient-specific in vitro models. iPSC technology is less than a decade old but holds great promise for bridging the gaps between patients, genetics and biology. Despite many obvious advantages, iPSC studies still present multiple challenges. In this expert review, we critically review the challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes.Molecular Psychiatry advance online publication, 31 May 2016; doi:10.1038/mp.2016.89.

PMID: 27240529 [PubMed - as supplied by publisher]

Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin.

June 1, 2016 - 11:10am
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Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin.

Cell. 2016 Jan 14;164(1-2):183-96

Authors: Singh SK, Stogsdill JA, Pulimood NS, Dingsdale H, Kim YH, Pilaz LJ, Kim IH, Manhaes AC, Rodrigues WS, Pamukcu A, Enustun E, Ertuz Z, Scheiffele P, Soderling SH, Silver DL, Ji RR, Medina AE, Eroglu C

Abstract
Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism.

PMID: 26771491 [PubMed - indexed for MEDLINE]

The 15q13.3 deletion syndrome: Deficient α(7)-containing nicotinic acetylcholine receptor-mediated neurotransmission in the pathogenesis of neurodevelopmental disorders.

June 1, 2016 - 11:10am
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The 15q13.3 deletion syndrome: Deficient α(7)-containing nicotinic acetylcholine receptor-mediated neurotransmission in the pathogenesis of neurodevelopmental disorders.

Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jan 4;64:109-17

Authors: Deutsch SI, Burket JA, Benson AD, Urbano MR

Abstract
Array comparative genomic hybridization (array CGH) has led to the identification of microdeletions of the proximal region of chromosome 15q between breakpoints (BP) 3 or BP4 and BP5 encompassing CHRNA7, the gene encoding the α7-nicotinic acetylcholine receptor (α7nAChR) subunit. Phenotypic manifestations of persons with these microdeletions are variable and some heterozygous carriers are seemingly unaffected, consistent with their variable expressivity and incomplete penetrance. Nonetheless, the 15q13.3 deletion syndrome is associated with several neuropsychiatric disorders, including idiopathic generalized epilepsy, intellectual disability, autism spectrum disorders (ASDs) and schizophrenia. Haploinsufficient expression of CHRNA7 in this syndrome has highlighted important roles the α7nAChR plays in the developing brain and normal processes of attention, cognition, memory and behavior throughout life. Importantly, the existence of the 15q13.3 deletion syndrome contributes to an emerging literature supporting clinical trials therapeutically targeting the α7nAChR in disorders such as ASDs and schizophrenia, including the larger population of patients with no evidence of haploinsufficient expression of CHRNA7. Translational clinical trials will be facilitated by the existence of positive allosteric modulators (PAMs) of the α7nAChR that act at sites on the receptor distinct from the orthosteric site that binds acetylcholine and choline, the receptor's endogenous ligands. PAMs lack intrinsic efficacy by themselves, but act where and when the endogenous ligands are released in response to relevant social and cognitive provocations to increase the likelihood they will result in α7nAChR ion channel activation.

PMID: 26257138 [PubMed - indexed for MEDLINE]

Perception of emotion in facial stimuli: The interaction of ADRA2A and COMT genotypes, and sex.

June 1, 2016 - 11:10am
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Perception of emotion in facial stimuli: The interaction of ADRA2A and COMT genotypes, and sex.

Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jan 4;64:87-95

Authors: Tamm G, Kreegipuu K, Harro J

Abstract
Emotional facial stimuli are important social signals that are essential to be perceived and recognized in order to make appropriate decisions and responses in everyday communication. The ability to voluntarily guide attention to perceive and recognize emotions, and react to them varies largely across individuals, and has a strong genetic component (Friedman et al., 2008). Two key genetic variants of the catecholamine system that have been related to emotion perception and attention are the catechol-O-methyl transferase genetic variant (COMT Val158Met) and the α2A-receptor gene promoter polymorphism (ADRA2A C-1291G) accordingly. So far, the interaction of the two with sex in emotion perception has not been studied. Multilevel modeling method was applied to study how COMT Val158Met, ADRA2A C-1291G and sex are associated with measures of emotion perception in a large sample of young adults. Participants (n=506) completed emotion recognition and behavioral emotion detection tasks. It was found that COMT Val158Met genotype in combination with the ADRA2A C-1291G and sex predicts emotion detection, and perception of valence and arousal. In simple visual detection, the ADRA2A C-1291G G-allele leads to slower detection of a highly arousing face (scheming), which is modulated by each additional COMT Val158Met Met-allele and male sex predicting faster responses. The combination of G-allele, Met-allele and male sex also predicts higher perceived negativity in sad faces. No effects of C-1291G, Val158Met, and sex were found on verbal emotion recognition. Applying the findings to study the interplay between catecholamine-O-methyl transferase activity and α2A-receptors in emotion perception disorders (such as ADHD, autism and schizophrenia) in men and women would be the next step towards understanding individual differences in emotion perception.

PMID: 26234518 [PubMed - indexed for MEDLINE]

Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency.

June 1, 2016 - 11:10am
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Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency.

Hum Mol Genet. 2015 Sep 15;24(18):5250-9

Authors: Tan C, Shard C, Ranieri E, Hynes K, Pham DH, Leach D, Buchanan G, Corbett M, Shoubridge C, Kumar R, Douglas E, Nguyen LS, Mcmahon J, Sadleir L, Specchio N, Marini C, Guerrini R, Moller RS, Depienne C, Haan E, Thomas PQ, Berkovic SF, Scheffer IE, Gecz J

Abstract
Protocadherin 19 (PCDH19) female limited epilepsy (PCDH19-FE; also known as epilepsy and mental retardation limited to females, EFMR; MIM300088) is an infantile onset epilepsy syndrome with or without intellectual disability (ID) and autism. We investigated transcriptomes of PCDH19-FE female and control primary skin fibroblasts, which are endowed to metabolize neurosteroid hormones. We identified a set of 94 significantly dysregulated genes in PCDH19-FE females. Intriguingly, 43 of the 94 genes (45.7%) showed gender-biased expression; enrichment of such genes was highly significant (P = 2.51E-47, two-tailed Fisher exact test). We further investigated the AKR1C1-3 genes, which encode crucial steroid hormone-metabolizing enzymes whose key products include allopregnanolone and estradiol. Both mRNA and protein levels of AKR1C3 were significantly decreased in PCDH19-FE patients. In agreement with this, the blood levels of allopregnanolone were also (P < 0.01) reduced. In conclusion, we show that the deficiency of neurosteroid allopregnanolone, one of the most potent GABA receptor modulators, may contribute to PCDH19-FE. Overall our findings provide evidence for a role of neurosteroids in epilepsy, ID and autism and create realistic opportunities for targeted therapeutic interventions.

PMID: 26123493 [PubMed - indexed for MEDLINE]

Regulation of SPRY3 by X chromosome and PAR2-linked promoters in an autism susceptibility region.

June 1, 2016 - 11:10am
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Regulation of SPRY3 by X chromosome and PAR2-linked promoters in an autism susceptibility region.

Hum Mol Genet. 2015 Sep 15;24(18):5126-41

Authors: Ning Z, McLellan AS, Ball M, Wynne F, O'Neill C, Mills W, Quinn JP, Kleinjan DA, Anney RJ, Carmody RJ, O'Keeffe G, Moore T

Abstract
Sprouty proteins are regulators of cell growth and branching morphogenesis. Unlike mouse Spry3, which is X-linked, human SPRY3 maps to the pseudoautosomal region 2; however, the human Y-linked allele is not expressed due to epigenetic silencing by an unknown mechanism. SPRY3 maps adjacent to X-linked Trimethyllysine hydroxylase epsilon (TMLHE), recently identified as an autism susceptibility gene. We report that Spry3 is highly expressed in central and peripheral nervous system ganglion cells in mouse and human, including cerebellar Purkinje cells and retinal ganglion cells. Transient over-expression or knockdown of Spry3 in cultured mouse superior cervical ganglion cells inhibits and promotes, respectively, neurite growth and branching. A 0.7 kb gene fragment spanning the human SPRY3 transcriptional start site recapitulates the endogenous Spry3-expression pattern in LacZ reporter mice. In the human and mouse the SPRY3 promoter contains an AG-rich repeat and we found co-expression, and promoter binding and/or regulation of SPRY3 expression by transcription factors MAZ, EGR1, ZNF263 and PAX6. We identified eight alleles of the human SPRY3 promoter repeat in Caucasians, and similar allele frequencies in autism families. We characterized multiple SPRY3 transcripts originating at two CpG islands in the X-linked F8A3-TMLHE region, suggesting X chromosome regulation of SPRY3. These findings provide an explanation for differential regulation of X and Y-linked SPRY3 alleles. In addition, the presence of a SPRY3 transcript exon in a previously described X chromosome deletion associated with autism, and the cerebellar interlobular variation in Spry3 expression coincident with the reported pattern of Purkinje cell loss in autism, suggest SPRY3 as a candidate susceptibility locus for autism.

PMID: 26089202 [PubMed - indexed for MEDLINE]

Detection of Chromosomal Aberrations in Clinical Practice: From Karyotype to Genome Sequence.

June 1, 2016 - 11:10am
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Detection of Chromosomal Aberrations in Clinical Practice: From Karyotype to Genome Sequence.

Annu Rev Genomics Hum Genet. 2015;16:309-26

Authors: Martin CL, Warburton D

Abstract
Since the inception of clinical cytogenetics in the late 1950s, the field has witnessed the evolution of multiple methodologies for the evaluation of chromosomal imbalances and rearrangements. From the replacement of solidly stained chromosomes by Giemsa banding (G-banding) to in situ hybridization and microarrays, each technique has sought to detect smaller and smaller chromosomal aberrations across the genome. Microarray analysis has revealed that copy-number variants-a class of mutation resulting from the loss (deletion) or gain (duplication) of genomic material that is >1 kb in size-are among the significant contributors to human disease and normal variation. Here, we evaluate the history and utility of various methodologies and their impact on the current practice of clinical cytogenetics.

PMID: 26077817 [PubMed - indexed for MEDLINE]

Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum disorder.

May 31, 2016 - 8:05am

Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum disorder.

Eur J Med Genet. 2016 May 26;

Authors: Bhat G, LaGrave D, Millson A, Herriges J, Lamb AN, Matalon R

Abstract
We report an 8-year-old female with autism spectrum disorder (ASD), intellectual disability and speech delay who was found to carry a de novo 82 kb deletion of chromosome Xq11.1-11.2 involving the ARHGEF9 gene on chromosomal microarray. So far, 11 patients with point mutations, disruptions due to chromosomal rearrangements and deletions involving ARHGEF9 have been reported in the literature. ARHGEF9-related disorders comprise a wide phenotypic spectrum, including behavior disorders, autism spectrum disorder, intellectual disability, hyperekplexia and infantile epileptic encephalopathy. ARHGEF9 encodes for collybistin which plays an important role in post synaptic clustering of glycine and inhibitory gamma-aminobutyric acid receptors along with its scaffolding partner, gephyrin. The reduction of inhibitory receptor clusters in brain has been proposed as a plausible underlying pathophysiological mechanism. With this report, we provide further evidence for the role of ARHGEF9 in neurocognitive function, its implication in ASD, and review the clinical features of previously published individuals with ARHGEF9-related intellectual disability.

PMID: 27238888 [PubMed - as supplied by publisher]

Rab3 interacting molecule 3 mutations associated with autism alter regulation of voltage-dependent Ca²⁺ channels.

May 31, 2016 - 8:05am
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Rab3 interacting molecule 3 mutations associated with autism alter regulation of voltage-dependent Ca²⁺ channels.

Cell Calcium. 2015 Sep;58(3):296-306

Authors: Takada Y, Hirano M, Kiyonaka S, Ueda Y, Yamaguchi K, Nakahara K, Mori MX, Mori Y

Abstract
Autism is a neurodevelopmental psychiatric disorder characterized by impaired reciprocal social interaction, disrupted communication, and restricted and stereotyped patterns of interests. Autism is known to have a strong genetic component. Although mutations in several genes account for only a small proportion of individuals with autism, they provide insight into potential biological mechanisms that underlie autism, such as dysfunction in Ca(2+) signaling, synaptic dysfunction, and abnormal brain connectivity. In autism patients, two mutations have been reported in the Rab3 interacting molecule 3 (RIM3) gene. We have previously demonstrated that RIM3 physically and functionally interacts with voltage-dependent Ca(2+) channels (VDCCs) expressed in neurons via the β subunits, and increases neurotransmitter release. Here, by introducing corresponding autism-associated mutations that replace glutamic acid residue 176 with alanine (E176A) and methionine residue 259 with valine (M259V) into the C2B domain of mouse RIM3, we demonstrate that both mutations partly cancel the suppressive RIM3 effect on voltage-dependent inactivation of Ba(2+) currents through P/Q-type CaV2.1 recombinantly expressed in HEK293 cells. In recombinant N-type CaV2.2 VDCCs, the attenuation of the suppressive RIM3 effect on voltage-dependent inactivation is conserved for M259V but not E176A. Slowing of activation speed of P/Q-type CaV2.1 currents by RIM3 is abolished in E176A, while the physical interaction between RIM3 and β subunits is significantly attenuated in M259V. Moreover, increases by RIM3 in depolarization-induced Ca(2+) influx and acetylcholine release are significantly attenuated by E176A in rat pheochromocytoma PC12 cells. Thus, our data raise the interesting possibility that autism phenotypes are elicited by synaptic dysfunction via altered regulation of presynaptic VDCC function and neurotransmitter release.

PMID: 26142343 [PubMed - indexed for MEDLINE]

Brief Report: SETD2 Mutation in a Child with Autism, Intellectual Disabilities and Epilepsy.

May 31, 2016 - 8:05am
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Brief Report: SETD2 Mutation in a Child with Autism, Intellectual Disabilities and Epilepsy.

J Autism Dev Disord. 2015 Nov;45(11):3764-70

Authors: Lumish HS, Wynn J, Devinsky O, Chung WK

Abstract
Whole exome sequencing (WES) has been utilized with increasing frequency to identify mutations underlying rare diseases. Autism spectrum disorders (ASD) and intellectual disability (ID) are genetically heterogeneous, and novel genes for these disorders are rapidly being identified, making these disorders ideal candidates for WES. Here we report a 17-year-old girl with ASD, developmental delay, ID, seizures, Chiari I malformation, macrocephaly, and short stature. She was found by WES to have a de novo c.2028delT (P677LfsX19) mutation in the SET domain-containing protein 2 (SETD2) gene, predicted to be gene-damaging. This case offers evidence for the potential the role of SETD2 in ASD and ID and provides further detail about the phenotypic manifestations of mutations in SETD2.

PMID: 26084711 [PubMed - indexed for MEDLINE]

Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder.

May 29, 2016 - 7:56am

Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder.

Kidney Int. 2016 May 24;

Authors: Clissold RL, Shaw-Smith C, Turnpenny P, Bunce B, Bockenhauer D, Kerecuk L, Waller S, Bowman P, Ford T, Ellard S, Hattersley AT, Bingham C

Abstract
Heterozygous mutations of the HNF1B gene are the commonest known monogenic cause of developmental kidney disease. Half of patients have a deletion (approximately 1.3 Mb) of chromosome 17q12, encompassing HNF1B plus 14 additional genes. This 17q12 deletion has been linked with an increased risk of neurodevelopmental disorders, such as autism. Here we compared the neurodevelopmental phenotype of 38 patients with HNF1B-associated renal disease due to an intragenic mutation in 18 patients or due to 17q12 deletion in 20 patients to determine whether haploinsufficiency of HNF1B is responsible for the neurodevelopmental phenotype. Significantly, brief behavioral screening in children with the deletion showed high levels of psychopathology and its impact. Eight individuals (40%) with a deletion had a clinical diagnosis of a neurodevelopmental disorder compared to none with an intragenic mutation. The 17q12 deletions were also associated with more autistic traits. Two independent clinical geneticists were able to predict the presence of a deletion with a sensitivity of 83% and specificity of 79% when assessing facial dysmorphic features as a whole. Thus, the 17q12 deletions but not HNF1B intragenic mutations are associated with neurodevelopmental disorders. Hence, the HNF1B gene is not involved in the neurodevelopmental phenotype of these patients. Nephrologists need to be aware of this association to ensure appropriate referral to psychiatric services.

PMID: 27234567 [PubMed - as supplied by publisher]

Angelman Syndrome Protein Ube3a Regulates Synaptic Growth and Endocytosis by Inhibiting BMP Signaling in Drosophila.

May 28, 2016 - 7:55am

Angelman Syndrome Protein Ube3a Regulates Synaptic Growth and Endocytosis by Inhibiting BMP Signaling in Drosophila.

PLoS Genet. 2016 May;12(5):e1006062

Authors: Li W, Yao A, Zhi H, Kaur K, Zhu YC, Jia M, Zhao H, Wang Q, Jin S, Zhao G, Xiong ZQ, Zhang YQ

Abstract
Altered expression of the E3 ubiquitin ligase UBE3A, which is involved in protein degradation through the proteasome-mediated pathway, is associated with neurodevelopmental and behavioral defects observed in Angelman syndrome (AS) and autism. However, little is known about the neuronal function of UBE3A and the pathogenesis of UBE3A-associated disorders. To understand the in vivo function of UBE3A in the nervous system, we generated multiple mutations of ube3a, the Drosophila ortholog of UBE3A. We found a significantly increased number of total boutons and satellite boutons in conjunction with compromised endocytosis in the neuromuscular junctions (NMJs) of ube3a mutants compared to the wild type. Genetic and biochemical analysis showed upregulation of bone morphogenetic protein (BMP) signaling in the nervous system of ube3a mutants. An immunochemical study revealed a specific increase in the protein level of Thickveins (Tkv), a type I BMP receptor, but not other BMP receptors Wishful thinking (Wit) and Saxophone (Sax), in ube3a mutants. Ube3a was associated with and specifically ubiquitinated lysine 227 within the cytoplasmic tail of Tkv, and promoted its proteasomal degradation in Schneider 2 cells. Negative regulation of Tkv by Ube3a was conserved in mammalian cells. These results reveal a critical role for Ube3a in regulating NMJ synapse development by repressing BMP signaling. This study sheds new light onto the neuronal functions of UBE3A and provides novel perspectives for understanding the pathogenesis of UBE3A-associated disorders.

PMID: 27232889 [PubMed - as supplied by publisher]

α5GABAA receptor deficiency causes autism-like behaviors.

May 28, 2016 - 7:55am

α5GABAA receptor deficiency causes autism-like behaviors.

Ann Clin Transl Neurol. 2016 May;3(5):392-8

Authors: Zurek AA, Kemp SW, Aga Z, Walker S, Milenkovic M, Ramsey AJ, Sibille E, Scherer SW, Orser BA

Abstract
The prevalence of autism spectrum disorders (ASDs), which affect over 1% of the population, has increased twofold in recent years. Reduced expression of GABAA receptors has been observed in postmortem brain tissue and neuroimaging of individuals with ASDs. We found that deletion of the gene for the α5 subunit of the GABAA receptor caused robust autism-like behaviors in mice, including reduced social contacts and vocalizations. Screening of human exome sequencing data from 396 ASD subjects revealed potential missense mutations in GABRA5 and in RDX, the gene for the α5GABAA receptor-anchoring protein radixin, further supporting a α5GABAA receptor deficiency in ASDs.

PMID: 27231709 [PubMed]

Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications.

May 28, 2016 - 7:55am
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Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications.

Acta Neuropathol Commun. 2015;3:63

Authors: Wegiel J, Flory M, Schanen NC, Cook EH, Nowicki K, Kuchna I, Imaki H, Ma SY, Wegiel J, London E, Casanova MF, Wisniewski T, Brown WT

Abstract
INTRODUCTION: Autism is diagnosed in numerous genetic and genomic developmental disorders associated with an overlap in high-risk genes and loci that underlie intellectual disability (ID) and epilepsy. The aim of this stereological study of neuronal soma volume in 25 brain structures and their subdivisions in eight individuals 9 to 26 years of age who were diagnosed with chromosome 15q11.2-13.1 duplication syndrome [dup(15)], autism, ID and epilepsy; eight age-matched subjects diagnosed with autism of unknown etiology (idiopathic autism) and seven control individuals was to establish whether defects of neuronal soma growth are a common denominator of developmental pathology in idiopathic and syndromic autism and how genetic modifications alter the trajectory of neuronal soma growth in dup(15) autism.
RESULTS: Application of the Nucleator software to estimate neuronal size revealed significant neuronal soma volume deficits in 11 of 25 structures and their subregions (44 %) in subjects diagnosed with dup(15) autism, including consistent neuronal soma volume deficits in the limbic system (sectors CA2, 3 and 4 in Ammon's horn, the second and third layers of the entorhinal cortex and in the amygdala), as well as in the thalamus, nucleus accumbens, external globus pallidus, and Ch3 nucleus in the magnocellular basal complex, and in the inferior olive in the brainstem. The second feature distinguishing dup(15) autism was persistent neuronal soma deficits in adolescents and young adults, whereas in idiopathic autism, neuronal volume deficit is most prominent in 4- to 8-year-old children but affects only a few brain regions in older subjects.
CONCLUSIONS: This study demonstrates that alterations in the trajectory of neuronal growth throughout the lifespan are a core pathological features of idiopathic and syndromic autism. However, dup(15) causes persistent neuronal volume deficits in adolescence and adulthood, with prominent neuronal growth deficits in all major compartments of the limbic system. The more severe neuronal nuclear and cytoplasic volume deficits in syndromic autism found in this study and the more severe focal developmental defects in the limbic system in dup(15) previously reported in this cohort may contribute to the high prevalence of early onset intractable epilepsy and sudden unexpected death in epilepsy.

PMID: 26463344 [PubMed - indexed for MEDLINE]

Tuberous sclerosis complex.

May 27, 2016 - 7:53am
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Tuberous sclerosis complex.

Nat Rev Dis Primers. 2016;2:16035

Authors: Henske EP, Jóźwiak S, Kingswood JC, Sampson JR, Thiele EA

Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis. Remarkable progress in basic and translational research, in addition to several randomized controlled trials worldwide, has led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary lymphangioleiomyomatosis, but further research is needed to establish full indications of therapeutic treatment. In this Primer, we review the state-of-the-art knowledge in the TSC field, including the molecular and cellular basis of the disease, medical management, major knowledge gaps and ongoing research towards a cure.

PMID: 27226234 [PubMed - in process]

Association of oligodendrocytes differentiation regulator gene DUSP15 with autism.

May 26, 2016 - 7:49am

Association of oligodendrocytes differentiation regulator gene DUSP15 with autism.

World J Biol Psychiatry. 2016 May 25;:1-8

Authors: Tian Y, Wang L, Jia M, Lu T, Ruan Y, Wu Z, Wang L, Liu J, Zhang D

Abstract
OBJECTIVES: Autism is a pervasive neurodevelopmental disorder with high heritability. Genetic factors play crucial roles in the aetiology of autism. Dual specificity phosphatase 15 (DUSP15) has been recognised as a key regulator gene for oligodendrocytes differentiation. A previous study detected one de novo missense variant (p.Thr107Met) with probable deleterious function in exon 6 of DUSP15 among patients with autism. Therefore, we sequenced this mutation in autistic children and performed an association analysis between DUSP15 polymorphisms and autism.
METHODS: We performed a case-control study between 255 children affected with autism and 427 healthy controls. Four tag-single nucleotide polymorphisms (SNPs) were selected. These SNPs and the previously reported mutation in exon 6 of DUSP15 were genotyped via Sanger sequencing.
RESULTS: Our results showed that rs3746599 was significantly associated with autism under allelic, additive and dominant models, respectively (χ(2 )=( )9.699, P = 0.0018; χ(2 )=( )16.224, P = 0.001; χ(2 )=( )7.198, P = 0.007). The association remained significant after Bonferroni correction and permutation tests (n = 10,000). We did not detect the missense variant p.Thr107Met reported in previous studies. However, a de novo missense variant of DUSP15 (p.Ala56Thr) with a probable disease-causing effect was detected in one autistic child while absent in healthy controls.
CONCLUSIONS: Our findings initially suggest that DUSP15 might be a susceptibility gene for autism in Chinese Han population.

PMID: 27223645 [PubMed - as supplied by publisher]

The Psychological Impact of Prenatal Diagnosis and Disclosure of Susceptibility Loci: First Impressions of Parents' Experiences.

May 26, 2016 - 7:49am

The Psychological Impact of Prenatal Diagnosis and Disclosure of Susceptibility Loci: First Impressions of Parents' Experiences.

J Genet Couns. 2016 May 25;

Authors: van der Steen SL, Riedijk SR, Verhagen-Visser J, Govaerts LC, Srebniak MI, Van Opstal D, Joosten M, Knapen MF, Tibben A, Diderich KE, Galjaard RJ

Abstract
Genomic microarray may detect susceptibility loci (SL) for neurodevelopmental disorders such as autism and epilepsy, with a yet unquantifiable risk for the fetus. The prenatal disclosure of susceptibility loci is a topic of much debate. Many health care professionals fear that reporting susceptibility loci may put a psychological burden on pregnant couples. It is our policy to disclose prenatal susceptibility loci as we recognize them as actionable for prospective parents. The aim of this report was to evaluate the psychological impact of disclosing a prenatal diagnosis of susceptibility loci. The psychological impact of disclosing susceptibility loci was evaluated in the first patients who received such results. Eight out of 15 women who had a susceptibility locus disclosed and four of their partners consented to share their experiences through a telephonic evaluation (n = 12). Follow-up time ranged from 3 to 15 months after their prenatal test result. The reporting of susceptibility loci was initially 'shocking' for five parents while the other seven felt 'worried'. Ten out of 12 participants indicated they would like to be informed about the susceptibility locus again, two were unsure. Most had no enduring worries. Participants unanimously indicated that pregnant couples should have an individualized pre-test choice about susceptibility loci (non)disclosure. We observed no negative psychological impact with the prenatal diagnosis and disclosure of SL on participants. A key factor in mitigating parental anxiety with SL disclosure appears to be post-test genetic counseling. Our report confirms that pregnant women and their partners prefer an individualized choice regarding the scope of prenatal testing.

PMID: 27220741 [PubMed - as supplied by publisher]

Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects.

May 26, 2016 - 7:49am
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Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects.

Neuron. 2016 Jan 6;89(1):147-62

Authors: Zhou Y, Kaiser T, Monteiro P, Zhang X, Van der Goes MS, Wang D, Barak B, Zeng M, Li C, Lu C, Wells M, Amaya A, Nguyen S, Lewis M, Sanjana N, Zhou Y, Zhang M, Zhang F, Fu Z, Feng G

Abstract
Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients.

PMID: 26687841 [PubMed - indexed for MEDLINE]

Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-Related Genes.

May 26, 2016 - 7:49am
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Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-Related Genes.

Neuron. 2016 Jan 6;89(1):113-28

Authors: Lee JA, Damianov A, Lin CH, Fontes M, Parikshak NN, Anderson ES, Geschwind DH, Black DL, Martin KC

Abstract
Human genetic studies have identified the neuronal RNA binding protein, Rbfox1, as a candidate gene for autism spectrum disorders. While Rbfox1 functions as a splicing regulator in the nucleus, it is also alternatively spliced to produce cytoplasmic isoforms. To investigate the function of cytoplasmic Rbfox1, we knocked down Rbfox proteins in mouse neurons and rescued with cytoplasmic or nuclear Rbfox1. Transcriptome profiling showed that nuclear Rbfox1 rescued splicing changes, whereas cytoplasmic Rbfox1 rescued changes in mRNA levels. iCLIP-seq of subcellular fractions revealed that Rbfox1 bound predominantly to introns in nascent RNA, while cytoplasmic Rbox1 bound to 3' UTRs. Cytoplasmic Rbfox1 binding increased target mRNA stability and translation, and Rbfox1 and miRNA binding sites overlapped significantly. Cytoplasmic Rbfox1 target mRNAs were enriched in genes involved in cortical development and autism. Our results uncover a new Rbfox1 regulatory network and highlight the importance of cytoplasmic RNA metabolism to cortical development and disease.

PMID: 26687839 [PubMed - indexed for MEDLINE]

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