pubmed: autism and genetics

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Autistic children display elevated urine levels of bovine casomorphin-7 immunoreactivity.

January 13, 2015 - 7:29am
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Autistic children display elevated urine levels of bovine casomorphin-7 immunoreactivity.

Peptides. 2014 Jun;56:68-71

Authors: Sokolov O, Kost N, Andreeva O, Korneeva E, Meshavkin V, Tarakanova Y, Dadayan A, Zolotarev Y, Grachev S, Mikheeva I, Varlamov O, Zozulya A

Abstract
Elevated concentrations of circulating casomorphins (CM), the exogenous opioid peptides from milk casein, may contribute to the pathogenesis of autism in children. Because several mass spectrometry studies failed to detect casomorphins in autistic children, it was questioned whether these peptides can be detected in body fluids by mass spec. Here we demonstrated, using a novel high sensitivity ELISA method, that autistic children have significantly higher levels of urine CM-7 than control children. The severity of autistic symptoms correlated with concentrations of CM-7 in the urine. Because CMs interact with opioid and serotonin receptors, the known modulators of synaptogenesis, we suggest that chronic exposure to elevated levels of bovine CMs may impair early child development, setting the stage for autistic disorders.

PMID: 24657283 [PubMed - indexed for MEDLINE]

Absence of strong strain effects in behavioral analyses of Shank3-deficient mice.

January 13, 2015 - 7:29am
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Absence of strong strain effects in behavioral analyses of Shank3-deficient mice.

Dis Model Mech. 2014 Jun;7(6):667-81

Authors: Drapeau E, Dorr NP, Elder GA, Buxbaum JD

Abstract
Haploinsufficiency of SHANK3, caused by chromosomal abnormalities or mutations that disrupt one copy of the gene, leads to a neurodevelopmental syndrome called Phelan-McDermid syndrome, symptoms of which can include absent or delayed speech, intellectual disability, neurological changes and autism spectrum disorders. The SHANK3 protein forms a key structural part of the post-synaptic density. We previously generated and characterized mice with a targeted disruption of Shank3 in which exons coding for the ankyrin-repeat domain were deleted and expression of full-length Shank3 was disrupted. We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions, in Shank3 heterozygous mice. Changes in phenotype owing to a mutation at a single locus are quite frequently modulated by other loci, most dramatically when the entire genetic background is changed. In mice, each strain of laboratory mouse represents a distinct genetic background and alterations in phenotype owing to gene knockout or transgenesis are frequently different across strains, which can lead to the identification of important modifier loci. We have investigated the effect of genetic background on phenotypes of Shank3 heterozygous, knockout and wild-type mice, using C57BL/6, 129SVE and FVB/Ntac strain backgrounds. We focused on observable behaviors with the goal of carrying out subsequent analyses to identify modifier loci. Surprisingly, there were very modest strain effects over a large battery of analyses. These results indicate that behavioral phenotypes associated with Shank3 haploinsufficiency are largely strain-independent.

PMID: 24652766 [PubMed - indexed for MEDLINE]

Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production.

January 13, 2015 - 7:29am
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Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production.

Hum Mol Genet. 2014 Jun 15;23(12):3212-27

Authors: Tilot AK, Gaugler MK, Yu Q, Romigh T, Yu W, Miller RH, Frazier TW, Eng C

Abstract
PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal-dominant genetic condition underlying a subset of autism spectrum disorder (ASD) with macrocephaly. Caused by germline mutations in PTEN, PHTS also causes increased risks of multiple cancers via dysregulation of the PI3K and MAPK signaling pathways. Conditional knockout models have shown that neural Pten regulates social behavior, proliferation and cell size. Although much is known about how the intracellular localization of PTEN regulates signaling in cancer cell lines, we know little of how PTEN localization influences normal brain physiology and behavior. To address this, we generated a germline knock-in mouse model of cytoplasm-predominant Pten and characterized its behavioral and cellular phenotypes. The homozygous Pten(m3m4) mice have decreased total Pten levels including a specific drop in nuclear Pten and exhibit region-specific increases in brain weight. The Pten(m3m4) model displays sex-specific increases in social motivation, poor balance and normal recognition memory-a profile reminiscent of some individuals with high functioning ASD. The cytoplasm-predominant protein caused cellular hypertrophy limited to the soma and led to increased NG2 cell proliferation and accumulation of glia. The animals also exhibit significant astrogliosis and microglial activation, indicating a neuroinflammatory phenotype. At the signaling level, Pten(m3m4) mice show brain region-specific differences in Akt activation. These results demonstrate that differing alterations to the same autism-linked gene can cause distinct behavioral profiles. The Pten(m3m4) model is the first murine model of inappropriately elevated social motivation in the context of normal cognition and may expand the range of autism-related behaviors replicated in animal models.

PMID: 24470394 [PubMed - indexed for MEDLINE]

CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size.

January 13, 2015 - 7:29am
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CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size.

Hum Mol Genet. 2014 Jun 15;23(12):3228-38

Authors: Ludwig AL, Espinal GM, Pretto DI, Jamal AL, Arque G, Tassone F, Berman RF, Hagerman PJ

Abstract
Large expansions of a CGG-repeat element (>200 repeats; full mutation) in the fragile X mental retardation 1 (FMR1) gene cause fragile X syndrome (FXS), the leading single-gene form of intellectual disability and of autism spectrum disorder. Smaller expansions (55-200 CGG repeats; premutation) result in the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Whereas FXS is caused by gene silencing and insufficient FMR1 protein (FMRP), FXTAS is thought to be caused by 'toxicity' of expanded-CGG-repeat mRNA. However, as FMRP expression levels decrease with increasing CGG-repeat length, lowered protein may contribute to premutation-associated clinical involvement. To address this issue, we measured brain Fmr1 mRNA and FMRP levels as a function of CGG-repeat length in a congenic (CGG-repeat knock-in) mouse model using 57 wild-type and 97 expanded-CGG-repeat mice carrying up to ~250 CGG repeats. While Fmr1 message levels increased with repeat length, FMRP levels trended downward over the same range, subject to significant inter-subject variation. Human comparisons of protein levels in the frontal cortex of 7 normal and 17 FXTAS individuals revealed that the mild FMRP decrease in mice mirrored the more limited data for FMRP expression in the human samples. In addition, FMRP expression levels varied in a subset of mice across the cerebellum, frontal cortex, and hippocampus, as well as at different ages. These results provide a foundation for understanding both the CGG-repeat-dependence of FMRP expression and for interpreting clinical phenotypes in premutation carriers in terms of the balance between elevated mRNA and lowered FMRP expression levels.

PMID: 24463622 [PubMed - indexed for MEDLINE]

Possible association between the oxytocin receptor gene and N-acetylaspartate of the right medial temporal lobe in autism spectrum disorders.

January 13, 2015 - 7:29am
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Possible association between the oxytocin receptor gene and N-acetylaspartate of the right medial temporal lobe in autism spectrum disorders.

Psychiatry Clin Neurosci. 2014 Jan;68(1):83

Authors: Egawa J, Watanabe Y, Endo T, Kitamura H, Someya T

PMID: 24393355 [PubMed - indexed for MEDLINE]

Characterization of depression in children with autism spectrum disorders.

January 13, 2015 - 7:29am
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Characterization of depression in children with autism spectrum disorders.

J Dev Behav Pediatr. 2011 May;32(4):332-40

Authors: Magnuson KM, Constantino JN

Abstract
Depressive syndromes represent a disabling comorbidity for many children with autism spectrum disorders (ASD); however, the ascertainment of depression can be complicated by phenotypic overlap between the 2 conditions, by ways in which autistic symptomatology can mask cardinal features of depression and by atypical manifestations of depression in children with ASD. These issues have contributed to wide variation in the estimation of prevalence rates of depression in individuals with ASD and invoke the need for new approaches to the specific detection of depression and other neuropsychiatric comorbidities that aggregate in children affected by ASD. The authors review the scientific literature relevant to the occurrence of depression in ASD and consider important parameters of risk, including psychosocial factors such as insight into affectation status, as well as biological factors such as the aggregation of depressive syndromes in certain families affected by autism, which has suggested possible overlap in genetic influences underlying the 2 conditions. Variability in the manifestations of depression across environmental contexts provides important clues to intervention and underscores the potential importance of involving multiple informants in ascertaining depression in children and adolescents with ASD. A practical strategy for evaluating the presence of depression in youth with ASD is synthesized from the available data and discussed.

PMID: 21502871 [PubMed - indexed for MEDLINE]

Dihydropyrimidine Dehydrogenase Deficiency in Two Malaysian Siblings with Abnormal MRI Findings.

January 8, 2015 - 7:25am

Dihydropyrimidine Dehydrogenase Deficiency in Two Malaysian Siblings with Abnormal MRI Findings.

Mol Syndromol. 2014 Dec;5(6):299-303

Authors: Chen BC, Mohd Rawi R, Meinsma R, Meijer J, Hennekam RC, van Kuilenburg AB

Abstract
Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of the pyrimidine metabolism. Deficiency of this enzyme leads to an accumulation of thymine and uracil and a deficiency of metabolites distal to the catabolic enzyme. The disorder presents with a wide clinical spectrum, ranging from asymptomatic to severe neurological manifestations, including intellectual disability, seizures, microcephaly, autistic behavior, and eye abnormalities. Here, we report on an 11-year-old Malaysian girl and her 6-year-old brother with DPD deficiency who presented with intellectual disability, microcephaly, and hypotonia. Brain MRI scans showed generalized cerebral and cerebellar atrophy and callosal body dysgenesis in the boy. Urine analysis showed strongly elevated levels of uracil in the girl and boy (571 and 578 mmol/mol creatinine, respectively) and thymine (425 and 427 mmol/mol creatinine, respectively). Sequence analysis of the DPYD gene showed that both siblings were homozygous for the mutation c.1651G>A (pAla551Thr).

PMID: 25565930 [PubMed - as supplied by publisher]

Association of dopamine gene variants, emotion dysregulation and ADHD in autism spectrum disorder.

January 8, 2015 - 7:25am
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Association of dopamine gene variants, emotion dysregulation and ADHD in autism spectrum disorder.

Res Dev Disabil. 2014 Jul;35(7):1658-65

Authors: Gadow KD, Pinsonneault JK, Perlman G, Sadee W

Abstract
The aim of the present study was to evaluate the association of dopaminergic gene variants with emotion dysregulation (EMD) and attention-deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorder (ASD). Three dopamine transporter gene (SLC6A3/DAT1) polymorphisms (intron8 5/6 VNTR, 3'-UTR 9/10 VNTR, rs27072 in the 3'-UTR) and one dopamine D2 receptor gene (DRD2) variant (rs2283265) were selected for genotyping based on à priori evidence of regulatory activity or, in the case of DAT1 9/10 VNTR, commonly reported associations with ADHD. A sample of 110 children with ASD was assessed with a rigorously validated DSM-IV-referenced rating scale. Global EMD severity (parents' ratings) was associated with DAT1 intron8 (ηp(2)=.063) and rs2283265 (ηp(2)=.044). Findings for DAT1 intron8 were also significant for two EMD subscales, generalized anxiety (ηp(2)=.065) and depression (ηp(2)=.059), and for DRD2 rs2283265, depression (ηp(2)=.053). DRD2 rs2283265 was associated with teachers' global ratings of ADHD (ηp(2)=.052). DAT1 intron8 was associated with parent-rated hyperactivity (ηp(2)=.045) and both DAT1 9/10 VNTR (ηp(2)=.105) and DRD2 rs2283265 (ηp(2)=.069) were associated with teacher-rated inattention. These findings suggest that dopaminergic gene polymorphisms may modulate EMD and ADHD symptoms in children with ASD but require replication with larger independent samples.

PMID: 24780147 [PubMed - indexed for MEDLINE]

Neurodevelopmental outcome in Angelman syndrome: genotype-phenotype correlations.

January 8, 2015 - 7:25am
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Neurodevelopmental outcome in Angelman syndrome: genotype-phenotype correlations.

Res Dev Disabil. 2014 Jul;35(7):1742-7

Authors: Mertz LG, Thaulov P, Trillingsgaard A, Christensen R, Vogel I, Hertz JM, Ostergaard JR

Abstract
Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, developmental delay, lack of speech, and epileptic seizures. Previous studies have indicated that children with AS due to 15q11.2-q13 deletions have a more severe developmental delay and present more often autistic features than those with AS caused by other genetic etiologies. The present study investigated the neurodevelopmental profiles of the different genetic etiologies of AS, and examined the evolution of mental development and autistic features over a 12-year period in children with a 15q11.2-q13 deletion. This study included 42 children with AS. Twelve had a Class I deletion, 18 had Class II deletions, three showed atypical large deletions, five had paternal uniparental disomy (pUPD) and four had UBE3A mutations. Children with a deletion (Class I and Class II) showed significantly reduced developmental age in terms of visual perception, receptive language, and expressive language when compared to those with a UBE3A mutation and pUPD. Within all subgroups, expressive language performance was significantly reduced when compared to the receptive performance. A follow-up study of seven AS cases with 15q11.2-q13 deletions revealed that over 12 years, the level of autistic features did not change, but both receptive and expressive language skills improved.

PMID: 24656292 [PubMed - indexed for MEDLINE]

Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the Automated Tube Test.

January 7, 2015 - 6:44am

Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the Automated Tube Test.

Neurobiol Dis. 2015 Jan 3;

Authors: Cef E, van den Berg WE, Ram B, Jaafar IA, Nieuwenhuizen-Bakker IM, Gasparini F, Kushner SA, Willemsen R

Abstract
Fragile X syndrome is the most common monogenetic form of intellectual disability and autism. Although the Fmr1 knockout mouse model recapitulates many aspects of the human FXS condition, the establishment of robust social behavioural phenotypes suitable for drug screening has been difficult. Here, we describe a novel social behavioural paradigm, the Automated Tube Test (ATT), for which Fmr1 knockout mice demonstrate a highly reliable and robust phenotype. Fmr1 KO mice show highly dominant behaviour over wild-type littermates in the ATT. Consistent with previous findings, we observed a highly significant, albeit partial, rescue of the altered social behaviour of Fmr1 knockout mice in the ATT, using genetic (mGluR5 deletion) or pharmacological inhibition (mGluR5 antagonist) of mGluR5 signalling independently. Together, our results validate the Automated Tube Test as a robust outcome measure for social behaviour in preclinical research for FXS, and confirm the pathophysiological relevance of mGluR5 signalling. Moreover, our findings highlight the strategy of initiating pharmacological intervention in adulthood as holding significant clinical potential.

PMID: 25562659 [PubMed - as supplied by publisher]

Identification and functional characterization of rare SHANK2 variants in schizophrenia.

January 7, 2015 - 6:44am

Identification and functional characterization of rare SHANK2 variants in schizophrenia.

Mol Psychiatry. 2015 Jan 6;

Authors: Peykov S, Berkel S, Schoen M, Weiss K, Degenhardt F, Strohmaier J, Weiss B, Proepper C, Schratt G, Nöthen MM, Boeckers TM, Rietschel M, Rappold GA

Abstract
Recent genetic data on schizophrenia (SCZ) have suggested that proteins of the postsynaptic density of excitatory synapses have a role in its etiology. Mutations in the three SHANK genes encoding for postsynaptic scaffolding proteins have been shown to represent risk factors for autism spectrum disorders and other neurodevelopmental disorders. To address if SHANK2 variants are associated with SCZ, we sequenced SHANK2 in 481 patients and 659 unaffected individuals. We identified a significant increase in the number of rare (minor allele frequency<1%) SHANK2 missense variants in SCZ individuals (6.9%) compared with controls (3.9%, P=0.039). Four out of fifteen non-synonymous variants identified in the SCZ cohort (S610Y, R958S, P1119T and A1731S) were selected for functional analysis. Overexpression and knockdown-rescue experiments were carried out in cultured primary hippocampal neurons with a major focus on the analysis of morphological changes. Furthermore, the effect on actin polymerization in fibroblast cell lines was investigated. All four variants revealed functional impairment to various degrees, as a consequence of alterations in spine volume and clustering at synapses and an overall loss of presynaptic contacts. The A1731S variant was identified in four unrelated SCZ patients (0.83%) but not in any of the sequenced controls and public databases (P=4.6 × 10(-5)). Patients with the A1731S variant share an early prodromal phase with an insidious onset of psychiatric symptoms. A1731S overexpression strongly decreased the SHANK2-Bassoon-positive synapse number and diminished the F/G-actin ratio. Our results strongly suggest a causative role of rare SHANK2 variants in SCZ and underline the contribution of SHANK2 gene mutations in a variety of neuropsychiatric disorders.Molecular Psychiatry advance online publication, 6 January 2015; doi:10.1038/mp.2014.172.

PMID: 25560758 [PubMed - as supplied by publisher]

[Genes, environment and autism spectrum disorders].

January 7, 2015 - 6:44am
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[Genes, environment and autism spectrum disorders].

Tijdschr Psychiatr. 2014;56(10):668-9

Authors: Staal W

PMID: 25327348 [PubMed - indexed for MEDLINE]

[The influence of genes and environment on the development of autism spectrum disorders].

January 7, 2015 - 6:44am
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[The influence of genes and environment on the development of autism spectrum disorders].

Tijdschr Psychiatr. 2014;56(10):660-7

Authors: Spek AA

Abstract
BACKGROUND: Autism spectrum disorders (asd) occur in 0,6% of the general population. On the basis of research in the 70s, 80s and 90s many experts came to the conclusion that asd were in fact genetically determined and were linked only slightly to environmental factors. Recent research, however, indicates that environmental factors really do play an important role.
AIM: To describe and identify the main trends in current research into the causes of asd.
METHOD: The literature was studied with the help of Medline, Cochrane, Web of Science and ScienceDirect.
RESULTS: Recent studies indicate that there is an underlying genetic cause in 35 to 60% of the cases of asd. Environmental factors play a greater role than previously thought and trigger the development of asd in people with a genetic vulnerability to asd. Not only is there evidence of risk factors for asd, but there is also evidence that certain factors protect against asd, for instance the use of folic acid before and during pregnancy.
CONCLUSION: asd are probably related to a combination of gene mutations and environmental factors and to the interactions between the two. Further research is needed into the genetic and environmental causes of asd.

PMID: 25327347 [PubMed - indexed for MEDLINE]

Activity-dependent regulation of release probability at excitatory hippocampal synapses: a crucial role of fragile X mental retardation protein in neurotransmission.

January 7, 2015 - 6:44am
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Activity-dependent regulation of release probability at excitatory hippocampal synapses: a crucial role of fragile X mental retardation protein in neurotransmission.

Eur J Neurosci. 2014 May;39(10):1602-12

Authors: Wang XS, Peng CZ, Cai WJ, Xia J, Jin D, Dai Y, Luo XG, Klyachko VA, Deng PY

Abstract
Transcriptional silencing of the Fmr1 gene encoding fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), the most common form of inherited intellectual disability and the leading genetic cause of autism. FMRP has been suggested to play important roles in regulating neurotransmission and short-term synaptic plasticity at excitatory hippocampal and cortical synapses. However, the origins and mechanisms of these FMRP actions remain incompletely understood, and the role of FMRP in regulating synaptic release probability and presynaptic function remains debated. Here we used variance-mean analysis and peak-scaled nonstationary variance analysis to examine changes in both presynaptic and postsynaptic parameters during repetitive activity at excitatory CA3-CA1 hippocampal synapses in a mouse model of FXS. Our analyses revealed that loss of FMRP did not affect the basal release probability or basal synaptic transmission, but caused an abnormally elevated release probability specifically during repetitive activity. These abnormalities were not accompanied by changes in excitatory postsynaptic current kinetics, quantal size or postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor conductance. Our results thus indicate that FMRP regulates neurotransmission at excitatory hippocampal synapses specifically during repetitive activity via modulation of release probability in a presynaptic manner. Our study suggests that FMRP function in regulating neurotransmitter release is an activity-dependent phenomenon that may contribute to the pathophysiology of FXS.

PMID: 24646437 [PubMed - indexed for MEDLINE]

Associations between oxytocin-related genes and autistic-like traits.

January 7, 2015 - 6:44am
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Associations between oxytocin-related genes and autistic-like traits.

Soc Neurosci. 2014;9(4):378-86

Authors: Hovey D, Zettergren A, Jonsson L, Melke J, Anckarsäter H, Lichtenstein P, Westberg L

Abstract
Oxytocin has repeatedly been shown to influence human behavior in social contexts; also, a relationship between oxytocin and the pathophysiology of autism spectrum disorder (ASD) has been suggested. In the present study, we investigated single-nucleotide polymorphisms (SNPs) in the oxytocin gene (OXT) and the genes for single-minded 1 (SIM1), aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) and cluster of differentiation 38 (CD38) in a population of 1771 children from the Child and Adolescent Twin Study in Sweden (CATSS). Statistical analyses were performed to investigate any association between SNPs and autistic-like traits (ALTs), measured through ASD scores in the Autism-Tics, ADHD and other Co-morbidities inventory. Firstly, we found a statistically significant association between the SIM1 SNP rs3734354 (Pro352Thr) and scores for language impairment (p = .0004), but due to low statistical power this should be interpreted cautiously. Furthermore, nominal associations were found between ASD scores and SNPs in OXT, ARNT2 and CD38. In summary, the present study lends support to the hypothesis that oxytocin and oxytocin neuron development may have an influence on the development of ALTs and suggests a new candidate gene in the search for the pathophysiology of ASD.

PMID: 24635660 [PubMed - indexed for MEDLINE]

Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy.

January 7, 2015 - 6:44am
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Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy.

Neurobiol Dis. 2014 Jul;67:88-96

Authors: Dejanovic B, Lal D, Catarino CB, Arjune S, Belaidi AA, Trucks H, Vollmar C, Surges R, Kunz WS, Motameny S, Altmüller J, Köhler A, Neubauer BA, Epicure Consortium, Nürnberg P, Noachtar S, Schwarz G, Sander T

Abstract
Gephyrin is a postsynaptic scaffolding protein, essential for the clustering of glycine and γ-aminobutyric acid type-A receptors (GABAARs) at inhibitory synapses. An impairment of GABAergic synaptic inhibition represents a key pathway of epileptogenesis. Recently, exonic microdeletions in the gephyrin (GPHN) gene have been associated with neurodevelopmental disorders including autism spectrum disorder, schizophrenia and epileptic seizures. Here we report the identification of novel exonic GPHN microdeletions in two patients with idiopathic generalized epilepsy (IGE), representing the most common group of genetically determined epilepsies. The identified GPHN microdeletions involve exons 5-9 (Δ5-9) and 2-3 (Δ2-3), both affecting the gephyrin G-domain. Molecular characterization of the GPHN Δ5-9 variant demonstrated that it perturbs the clustering of regular gephyrin at inhibitory synapses in cultured mouse hippocampal neurons in a dominant-negative manner, resulting in a significant loss of γ2-subunit containing GABAARs. GPHN Δ2-3 causes a frameshift resulting in a premature stop codon (p.V22Gfs*7) leading to haplo-insufficiency of the gene. Our results demonstrate that structural exonic microdeletions affecting the GPHN gene constitute a rare genetic risk factor for IGE and other neuropsychiatric disorders by an impairment of the GABAergic inhibitory synaptic transmission.

PMID: 24561070 [PubMed - indexed for MEDLINE]

Neurexins.

January 7, 2015 - 6:44am
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Neurexins.

Genome Biol. 2013;14(9):213

Authors: Reissner C, Runkel F, Missler M

Abstract
The neurexin family of cell adhesion proteins consists of three members in vertebrates and has homologs in several invertebrate species. In mammals, each neurexin gene encodes an α-neurexin in which the extracellular portion is long, and a β-neurexin in which the extracellular portion is short. As a result of alternative splicing, both major isoforms can be transcribed in many variants, contributing to distinct structural domains and variability. Neurexins act predominantly at the presynaptic terminal in neurons and play essential roles in neurotransmission and differentiation of synapses. Some of these functions require the formation of trans-synaptic complexes with postsynaptic proteins such as neuroligins, LRRTM proteins or cerebellin. In addition, rare mutations and copy-number variations of human neurexin genes have been linked to autism and schizophrenia, indicating that impairments of synaptic function sustained by neurexins and their binding partners maybe relevant to the pathomechanism of these debilitating diseases.

PMID: 24083347 [PubMed - indexed for MEDLINE]

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