pubmed: autism and genetics

Subscribe to pubmed: autism and genetics feed pubmed: autism and genetics
NCBI: db=pubmed; Term=autism AND genetics
Updated: 2 hours 16 min ago

Introduction of the human AVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic mice.

March 31, 2015 - 6:11am
Related Articles

Introduction of the human AVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic mice.

Dis Model Mech. 2014 Aug;7(8):1013-22

Authors: Charles R, Sakurai T, Takahashi N, Elder GA, Gama Sosa MA, Young LJ, Buxbaum JD

Abstract
Central arginine vasopressin receptor 1A (AVPR1A) modulates a wide range of behaviors, including stress management and territorial aggression, as well as social bonding and recognition. Inter- and intra-species variations in the expression pattern of AVPR1A in the brain and downstream differential behavioral phenotypes have been attributed to differences in the non-coding regions of the AVPR1A gene, including polymorphic elements within upstream regulatory areas. Gene association studies have suggested a link between AVPR1A polymorphisms and autism, and AVPR1A has emerged as a potential pharmacological target for treatment of social cognitive impairments and mood and anxiety disorders. To further investigate the genetic mechanism giving rise to species differences in AVPR1A expression patterns and associated social behaviors, and to create a preclinical mouse model useful for screening drugs targeting AVPR1A, we engineered and extensively characterized bacterial artificial chromosome (BAC) transgenic mice harboring the entire human AVPR1A locus with the surrounding regulatory elements. Compared with wild-type animals, the humanized mice displayed a more widely distributed ligand-AVPR1A binding pattern, which overlapped with that of primates. Furthermore, humanized AVPR1A mice displayed increased reciprocal social interactions compared with wild-type animals, but no differences in social approach and preference for social novelty were observed. Aspects of learning and memory, specifically novel object recognition and spatial relocation recognition, were unaffected. The biological alterations in humanized AVPR1A mice resulted in the rescue of the prepulse inhibition impairments that were observed in knockout mice, indicating conserved functionality. Although further behavioral paradigms and additional cohorts need to be examined in humanized AVPR1A mice, the results demonstrate that species-specific variations in the genomic content of regulatory regions surrounding the AVPR1A locus are responsible for differential receptor protein expression patterns across species and that they are likely to contribute to species-specific behavioral variation. The humanized AVPR1A mouse is a potential preclinical model for further understanding the regulation of receptor gene expression and the impact of variation in receptor expression on behaviors, and should be useful for screening drugs targeting human AVPR1A, taking advantage of the expression of human AVPR1A in human-relevant brain regions.

PMID: 24924430 [PubMed - indexed for MEDLINE]

Mutation screening of the neurexin 1 gene in thai patients with intellectual disability and autism spectrum disorder.

March 31, 2015 - 6:11am
Related Articles

Mutation screening of the neurexin 1 gene in thai patients with intellectual disability and autism spectrum disorder.

Genet Test Mol Biomarkers. 2014 Jul;18(7):510-5

Authors: Yangngam S, Plong-On O, Sripo T, Roongpraiwan R, Hansakunachai T, Wirojanan J, Sombuntham T, Ruangdaraganon N, Limprasert P

Abstract
AIM: Neurexin 1 has two major protein isoforms using alternative promoters, coding for the alpha-neurexin 1 (α-NRXN1) and beta-neurexin 1 (β-NRXN1) genes. This study is to explore the possibility that variants of the NRXN1 gene predispose to intellectual disability (ID) and autism spectrum disorder (ASD).
METHODS: The coding regions in 24 exons and exon-intron boundaries of the NRXN1 gene were investigated in 115 Thai patients with ID and ASD by direct DNA sequencing.
RESULTS: Nine novel variants of the NRXN1 gene were identified. Four novel variants were found in the β-NRXN1 gene, one variant of six GGC repeats in exon 1, and three variants at the 5'UTR. Five novel variants were identified in the α-NRXN1 gene, four intronic variants and one missense variant in exon 14 (c.2713T>A or p.F905I).
CONCLUSION: Mutation screening of the NRXN1gene in patients with ID and ASD may be useful to identify potential variants predisposing to ID and ASD. However, further studies utilizing protein functional analysis of the novel variants are required for a more definite conclusion.

PMID: 24832020 [PubMed - indexed for MEDLINE]

A 1.37-Mb 12p11.22-p11.21 deletion coincident with a 367-kb 22q11.2 duplication detected by array comparative genomic hybridization in an adolescent girl with autism and difficulty in self-care of menstruation.

March 31, 2015 - 6:11am
Related Articles

A 1.37-Mb 12p11.22-p11.21 deletion coincident with a 367-kb 22q11.2 duplication detected by array comparative genomic hybridization in an adolescent girl with autism and difficulty in self-care of menstruation.

Taiwan J Obstet Gynecol. 2014 Mar;53(1):74-8

Authors: Chen CP, Lin SP, Chern SR, Wu PS, Su JW, Lee CC, Wang W

Abstract
OBJECTIVE: To present an array comparative genomic hybridization (aCGH) characterization of a 12p11.22-p11.21 microdeletion and 22q11.2 microduplication in an adolescent girl with autism, mental retardation, facial dysmorphism, microcephaly, behavior problems, and an apparently balanced reciprocal translocation of t(8;12)(q24.3;p11.2).
MATERIALS AND METHODS: A 13-year-old girl was referred to the hospital because of autism, mental retardation, and difficulty in the self-care of her menstruation. Cytogenetic analysis revealed an apparently balanced reciprocal translocation and a karyotype of 46,XX,t(8;12) (q24.3;p11.2)dn. The girl manifested microcephaly, hypertelorism, flat facial profile, prominent forehead, thick scalp hair, upslanting palpebral fissures, broad nasal bridge, bulbous nose, right simian crease, bilateral clinodactyly of the fifth fingers, bilateral pes cavus, learning difficulties, mental retardation, emotional instability, cognitive impairment, behavior problems, jumping-like gaits, and autistic spectrum disorder. aCGH was performed to evaluate genomic imbalance in this patient.
RESULTS: aCGH analysis revealed a 1.37-Mb 12p11.22-p11.21 microdeletion or arr [hg 19] 12p11.22-p11.21 (30,645,008-32,014,774)×1 and a 367-kb 22q11.21 microduplication or arr [hg 19] 22q11.21 (18,657,470-19,024,306)×3. The 1.37-Mb 12p11.22-p11.21 microdeletion encompassed 26 genes including IPO8, CAPRIN2, and DDX11, and the 367-kb 22q11.21 microduplication encompassed 20 genes including USP18, DGCR6, PRODH, and DGCR2.
CONCLUSION: An apparently balanced translocation may be in fact affected by concurrent deletion and duplication in two different chromosomal regions. Our presentation provides information on diagnostic phenotype of 12p11.22-p11.21 microdeletion and 22q11.2 microduplication.

PMID: 24767651 [PubMed - indexed for MEDLINE]

An assessment of time involved in pre-test case review and counseling for a whole genome sequencing clinical research program.

March 31, 2015 - 6:11am
Related Articles

An assessment of time involved in pre-test case review and counseling for a whole genome sequencing clinical research program.

J Genet Couns. 2014 Aug;23(4):516-21

Authors: Williams JL, Faucett WA, Smith-Packard B, Wagner M, Williams MS

Abstract
Whole genome sequencing (WGS) is being used for evaluation of individuals with undiagnosed disease of suspected genetic origin. Implementing WGS into clinical practice will place an increased burden upon care teams with regard to pre-test patient education and counseling about results. To quantitate the time needed for appropriate pre-test evaluation of participants in WGS testing, we documented the time spent by our clinical research group on various activities related to program preparation, participant screening, and consent prior to WGS. Participants were children or young adults with autism, intellectual or developmental disability, and/or congenital anomalies, who have remained undiagnosed despite previous evaluation, and their biologic parents. Results showed that significant time was spent in securing allocation of clinical research space to counsel participants and families, and in acquisition and review of participant's medical records. Pre-enrollment chart review identified two individuals with existing diagnoses resulting in savings of $30,000 for the genome sequencing alone, as well as saving hours of personnel time for genome interpretation and communication of WGS results. New WGS programs should plan for costs associated with additional pre-test administrative planning and patient evaluation time that will be required to provide high quality care.

PMID: 24573557 [PubMed - indexed for MEDLINE]

Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women.

March 27, 2015 - 7:51am

Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women.

Neurology. 2015 Mar 25;

Authors: Cornish KM, Kraan CM, Bui QM, Bellgrove MA, Metcalfe SA, Trollor JN, Hocking DR, Slater HR, Inaba Y, Li X, Archibald AD, Turbitt E, Cohen J, Godler DE

Abstract
OBJECTIVE: To examine the epigenetic basis of psychiatric symptoms and dysexecutive impairments in FMR1 premutation (PM: 55 to 199 CGG repeats) women.
METHODS: A total of 35 FMR1 PM women aged between 22 and 55 years and 35 age- and IQ-matched women controls (CGG <45) participated in this study. All participants completed a range of executive function tests and self-reported symptoms of psychiatric disorders. The molecular measures included DNA methylation of the FMR1 CpG island in blood, presented as FMR1 activation ratio (AR), and 9 CpG sites located at the FMR1 exon1/intron 1 boundary, CGG size, and FMR1 mRNA levels.
RESULTS: We show that FMR1 intron 1 methylation levels could be used to dichotomize PM women into greater and lower risk categories (p = 0.006 to 0.037; odds ratio = 14-24.8), with only FMR1 intron 1 methylation, and to a lesser extent AR, being significantly correlated with the likelihood of probable dysexecutive or psychiatric symptoms (p < 0.05). Furthermore, the significant relationships between methylation and social anxiety were found to be mediated by executive function performance, but only in PM women. FMR1 exon 1 methylation, CGG size, and FMR1 mRNA could not predict probable dysexecutive/psychiatric disorders in PM women.
CONCLUSIONS: This is the first study supporting presence of specific epigenetic etiology associated with increased risk of developing comorbid dysexecutive and social anxiety symptoms in PM women. These findings could have implications for early intervention and risk estimate recommendations aimed at improving the outcomes for PM women and their families.

PMID: 25809302 [PubMed - as supplied by publisher]

"New insights into Brunner syndrome and potential for targeted therapy".

March 27, 2015 - 7:51am

"New insights into Brunner syndrome and potential for targeted therapy".

Clin Genet. 2015 Mar 23;

Authors: Palmer EE, Leffler M, Rogers C, Shaw M, Carroll R, Earl J, Cheung NW, Champion B, Hu H, Haas SA, Kalscheuer VM, Gecz J, Field M

Abstract
We report two families with Brunner syndrome living in one state of Australia. The first family had a predicted protein-truncating variant of MAOA (p.S251KfsX2). Affected males had mild intellectual disability (ID), obsessive behavior, limited friendships and were introverted and placid during clinical interview. The family disclosed episodic explosive aggression after a diagnosis was made. The second family had a missense variant in MAOA (p.R45W). Affected males had borderline-mild ID, attention deficit disorder and limited friendships. One had a history of explosive aggression in childhood, and episodic symptoms of flushing, headaches and diarrhoea. Their carrier mother had normal intelligence but similar episodic symptoms. Characteristic biochemical abnormalities included high serum serotonin and urinary metanephrines and low urinary 5-HIAA and VMA. Symptomatic individuals in the second family had particularly high serotonin levels and treatment with a serotonin reuptake inhibitor and dietary modification resulted in reversal of biochemical abnormalities, reduction of 'serotonergic' symptoms and behavioral improvement. Brunner syndrome should be considered as a cause of mild ID with paroxysmal behavioral symptoms. It can be screened for with serum/urine metanephrine and serotonin measurement. Cautious treatment with a serotonin reuptake inhibitor, dietary modifications and avoidance of medications contraindicated in patients on monoamine oxidase inhibitors can improve symptoms.

PMID: 25807999 [PubMed - as supplied by publisher]

Strong genetic influences on the stability of autistic traits in childhood.

March 27, 2015 - 7:51am
Related Articles

Strong genetic influences on the stability of autistic traits in childhood.

J Am Acad Child Adolesc Psychiatry. 2014 Feb;53(2):221-30

Authors: Holmboe K, Rijsdijk FV, Hallett V, Happé F, Plomin R, Ronald A

Abstract
OBJECTIVE: Disorders on the autism spectrum, as well as autistic traits in the general population, have been found to be both highly stable across age and highly heritable at individual ages. However, little is known about the overlap in genetic and environmental influences on autistic traits across age and the contribution of such influences to trait stability itself. The present study investigated these questions in a general population sample of twins.
METHOD: More than 6,000 twin pairs were rated on an established scale of autistic traits by their parents at 8, 9, and 12 years of age and by their teachers at 9 and 12 years of age. Data were analyzed using structural equation modeling.
RESULTS: The results indicated that, consistently across raters, not only were autistic traits stable, and moderately to highly heritable at individual ages, but there was also a high degree of overlap in genetic influences across age. Furthermore, autistic trait stability could largely be accounted for by genetic factors, with the environment unique to each twin playing a minor role. The environment shared by twins had virtually no effect on the longitudinal stability in autistic traits.
CONCLUSIONS: Autistic traits are highly stable across middle childhood. and this stability is caused primarily by genetic factors.

PMID: 24472256 [PubMed - indexed for MEDLINE]

Loss of δ-catenin function in severe autism.

March 26, 2015 - 7:06am

Loss of δ-catenin function in severe autism.

Nature. 2015 Mar 25;

Authors: Turner TN, Sharma K, Oh EC, Liu YP, Collins RL, Sosa MX, Auer DR, Brand H, Sanders SJ, Moreno-De-Luca D, Pihur V, Plona T, Pike K, Soppet DR, Smith MW, Cheung SW, Martin CL, State MW, Talkowski ME, Cook E, Huganir R, Katsanis N, Chakravarti A

Abstract
Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.

PMID: 25807484 [PubMed - as supplied by publisher]

[Dysregulation of the mTOR signaling pathway in the pathogenesis of autism spectrum disorders].

March 26, 2015 - 7:06am
Related Articles

[Dysregulation of the mTOR signaling pathway in the pathogenesis of autism spectrum disorders].

Postepy Hig Med Dosw (Online). 2014;68:375-83

Authors: Gabryel B, Kapałka A, Sobczyk W, Łabuzek K, Gawęda A, Janas-Kozik M

Abstract
Mammalian target of rapamycin (mTor) plays multiple role in central nervous system and is involved in regulation of cell viability, differentiation, transcription, translation, protein degradation, actin cytoskeletal organization and autophagy. Recent experimental and clinical studies reveal that disturbances of mTOR signaling are involved in the pathogenesis of autism spectrum disorders (ASD). This article reviews current data on the alteration in the mTOR transduction cascade, which may contribute to common neurobehavioral disorders typical for ASD. Moreover, the results of the latest experimental studies on the potential of mTOR inhibitors for the treatment of ASD are reviewed.

PMID: 24864089 [PubMed - indexed for MEDLINE]

High-Resolution Chromosome Ideogram Representation of Currently Recognized Genes for Autism Spectrum Disorders.

March 25, 2015 - 6:21am

High-Resolution Chromosome Ideogram Representation of Currently Recognized Genes for Autism Spectrum Disorders.

Int J Mol Sci. 2015;16(3):6464-6495

Authors: Butler MG, Rafi SK, Manzardo AM

Abstract
Recently, autism-related research has focused on the identification of various genes and disturbed pathways causing the genetically heterogeneous group of autism spectrum disorders (ASD). The list of autism-related genes has significantly increased due to better awareness with advances in genetic technology and expanding searchable genomic databases. We compiled a master list of known and clinically relevant autism spectrum disorder genes identified with supporting evidence from peer-reviewed medical literature sources by searching key words related to autism and genetics and from authoritative autism-related public access websites, such as the Simons Foundation Autism Research Institute autism genomic database dedicated to gene discovery and characterization. Our list consists of 792 genes arranged in alphabetical order in tabular form with gene symbols placed on high-resolution human chromosome ideograms, thereby enabling clinical and laboratory geneticists and genetic counsellors to access convenient visual images of the location and distribution of ASD genes. Meaningful correlations of the observed phenotype in patients with suspected/confirmed ASD gene(s) at the chromosome region or breakpoint band site can be made to inform diagnosis and gene-based personalized care and provide genetic counselling for families.

PMID: 25803107 [PubMed - as supplied by publisher]

Psychopathology and cognitive performance in individuals with membrane-associated guanylate kinase mutations: a functional network phenotyping study.

March 25, 2015 - 6:21am

Psychopathology and cognitive performance in individuals with membrane-associated guanylate kinase mutations: a functional network phenotyping study.

J Neurodev Disord. 2015;7(1):8

Authors: Baker K, Scerif G, Astle DE, Fletcher PC, Raymond FL

Abstract
BACKGROUND: Rare pathogenic variants in membrane-associated guanylate kinase (MAGUK) genes cause intellectual disability (ID) and have recently been associated with neuropsychiatric risk in the non-ID population. However, it is not known whether risk for psychiatric symptoms amongst individuals with ID due to MAGUK gene mutations is higher than expected for the degree of general intellectual impairment, nor whether specific cognitive differences are associated with disruption to this gene functional network.
METHODS: This study addresses these two questions via behavioural questionnaires and cognitive testing, applying quantitative methods previously validated in populations with ID. We compared males with X-linked ID caused by mutations in three MAGUK genes (PAK3, DLG3, OPHN1; n = 9) to males with ID caused by mutations in other X chromosome genes (n = 17). Non-parametric and parametric analyses were applied as appropriate to data.
RESULTS: Groups did not differ in age, global cognitive impairment, adaptive function or epilepsy prevalence. However, individuals with MAGUK gene mutations demonstrated significantly higher psychopathology risks, comprising elevated total problem behaviours, prominent hyperactivity and elevated scores on an autism screening checklist. Despite these overt difficulties, individuals in the MAGUK group performed more accurately than expected for age and intelligence quotient (IQ) on computerised tests of visual attention, convergent with mouse models of MAGUK loss-of-function.
CONCLUSIONS: Our findings support a role for MAGUK genes in influencing cognitive parameters relevant to psychiatric risk. In addition to establishing clear patterns of impairment for this group, our findings highlight the importance of careful phenotyping after genetic diagnosis, showing that gene functional network disruptions can be associated with specific psychopathological risks and cognitive differences within the context of ID.

PMID: 25802558 [PubMed]

Update on Autism Spectrum Disorder: Vaccines, Genomes, and Social Skills Training.

March 25, 2015 - 6:21am

Update on Autism Spectrum Disorder: Vaccines, Genomes, and Social Skills Training.

J Psychosoc Nurs Ment Health Serv. 2015 Mar 18;:1-4

Authors: McGuinness TM

Abstract
Despite making significant progress in understanding autism spectrum disorder (ASD) and its genetic underpinnings, controversy remains regarding ASD and its historical, erroneous association with vaccines. This controversy includes the latest anti-vaccine movement that caused a recurrence of the almost vanquished measles and mumps diseases. The history of ASD, complexities of research involving ASD genetics, and benefits of social skills training are explored. [Journal of Psychosocial Nursing and Mental Health Services, xx(xx), xx-xx.].

PMID: 25800558 [PubMed - as supplied by publisher]

SNAP25 is associated with schizophrenia and major depressive disorder in the Han Chinese population.

March 25, 2015 - 6:21am
Related Articles

SNAP25 is associated with schizophrenia and major depressive disorder in the Han Chinese population.

J Clin Psychiatry. 2015 Jan;76(1):e76-82

Authors: Wang Q, Wang Y, Ji W, Zhou G, He K, Li Z, Chen J, Li W, Wen Z, Shen J, Qiang Y, Ji J, Wang Y, Shi Y, Yi Q, Wang Y

Abstract
OBJECTIVE: Synaptosomal-associated protein of 25 kDa (SNAP25) is a member of the soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) protein complex, which plays essential roles in the modulation of different voltage-gated calcium channels and neurotransmitter release. Many previous studies have reported the SNAP25 gene to be significantly associated with attention-deficit/hyperactivity disorder (ADHD). Recently, shared genetic variants have been demonstrated in 5 major psychiatric disorders, including schizophrenia, major depressive disorder, bipolar disorder, autism spectrum disorders, and ADHD. However, no compelling, convincing evidence has suggested an association between SNAP25 and schizophrenia or major depressive disorder. Thus, we investigated the association between SNAP25 and both schizophrenia and major depressive disorder in the Han Chinese population.
METHOD: We performed a large-scale case-control study to test the association between SNAP25 and 2 major mental disorders, schizophrenia (DSM-IV criteria) and major depressive disorder (DSM-IV criteria), in the Han Chinese population. Seven single-nucleotide polymorphisms (SNPs) were genotyped in 1,330 schizophrenia patients, 1,045 major depressive disorder patients, and 1,520 healthy controls of Han Chinese origin.
RESULTS: Two SNPs, rs3787283 and rs3746544, were found to be associated with both schizophrenia (rs3746544, adjusted P = .00257) and major depressive disorder (rs3746544, adjusted P = .0485; rs3787283, adjusted P = .00387) in this study. The AG haplotype consisting of rs3787283 and rs3746544 was also significantly associated with both schizophrenia and major depressive disorder (schizophrenia: adjusted P = .0126; major depressive disorder: adjusted P = .000580). Additionally, we carried out a meta-analysis of the current data and published association results and further confirmed the association between rs3746544 and schizophrenia (Pmeta = .002, ORmeta = 1.213 [95% CI, 1.077-1.367]).
CONCLUSIONS: Our results indicated that SNPs in SNAP25 represented a common risk factor of both schizophrenia and major depressive disorder in the Han Chinese population.

PMID: 25650683 [PubMed - indexed for MEDLINE]

Hyperactivity of newborn Pten knock-out neurons results from increased excitatory synaptic drive.

March 25, 2015 - 6:21am
Related Articles

Hyperactivity of newborn Pten knock-out neurons results from increased excitatory synaptic drive.

J Neurosci. 2015 Jan 21;35(3):943-59

Authors: Williams MR, DeSpenza T, Li M, Gulledge AT, Luikart BW

Abstract
Developing neurons must regulate morphology, intrinsic excitability, and synaptogenesis to form neural circuits. When these processes go awry, disorders, including autism spectrum disorder (ASD) or epilepsy, may result. The phosphatase Pten is mutated in some patients having ASD and seizures, suggesting that its mutation disrupts neurological function in part through increasing neuronal activity. Supporting this idea, neuronal knock-out of Pten in mice can cause macrocephaly, behavioral changes similar to ASD, and seizures. However, the mechanisms through which excitability is enhanced following Pten depletion are unclear. Previous studies have separately shown that Pten-depleted neurons can drive seizures, receive elevated excitatory synaptic input, and have abnormal dendrites. We therefore tested the hypothesis that developing Pten-depleted neurons are hyperactive due to increased excitatory synaptogenesis using electrophysiology, calcium imaging, morphological analyses, and modeling. This was accomplished by coinjecting retroviruses to either "birthdate" or birthdate and knock-out Pten in granule neurons of the murine neonatal dentate gyrus. We found that Pten knock-out neurons, despite a rapid onset of hypertrophy, were more active in vivo. Pten knock-out neurons fired at more hyperpolarized membrane potentials, displayed greater peak spike rates, and were more sensitive to depolarizing synaptic input. The increased sensitivity of Pten knock-out neurons was due, in part, to a higher density of synapses located more proximal to the soma. We determined that increased synaptic drive was sufficient to drive hypertrophic Pten knock-out neurons beyond their altered action potential threshold. Thus, our work contributes a developmental mechanism for the increased activity of Pten-depleted neurons.

PMID: 25609613 [PubMed - indexed for MEDLINE]

Contribution of mGluR5 to pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion.

March 25, 2015 - 6:21am
Related Articles

Contribution of mGluR5 to pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion.

Nat Neurosci. 2015 Feb;18(2):182-4

Authors: Tian D, Stoppel LJ, Heynen AJ, Lindemann L, Jaeschke G, Mills AA, Bear MF

Abstract
Human chromosome 16p11.2 microdeletion is the most common gene copy number variation in autism, but the synaptic pathophysiology caused by this mutation is largely unknown. Using a mouse with the same genetic deficiency, we found that metabotropic glutamate receptor 5 (mGluR5)-dependent synaptic plasticity and protein synthesis was altered in the hippocampus and that hippocampus-dependent memory was impaired. Notably, chronic treatment with a negative allosteric modulator of mGluR5 reversed the cognitive deficit.

PMID: 25581360 [PubMed - indexed for MEDLINE]

The role of parental cognitive, behavioral, and motor profiles in clinical variability in individuals with chromosome 16p11.2 deletions.

March 25, 2015 - 6:21am
Related Articles

The role of parental cognitive, behavioral, and motor profiles in clinical variability in individuals with chromosome 16p11.2 deletions.

JAMA Psychiatry. 2015 Feb;72(2):119-26

Authors: Moreno-De-Luca A, Evans DW, Boomer KB, Hanson E, Bernier R, Goin-Kochel RP, Myers SM, Challman TD, Moreno-De-Luca D, Slane MM, Hare AE, Chung WK, Spiro JE, Faucett WA, Martin CL, Ledbetter DH

Abstract
IMPORTANCE: Most disorders caused by copy number variants (CNVs) display significant clinical variability, often referred to as incomplete penetrance and variable expressivity. Genetic and environmental sources of this variability are not well understood.
OBJECTIVES: To investigate the contributors to phenotypic variability in probands with CNVs involving the same genomic region; to measure the effect size for de novo mutation events; and to explore the contribution of familial background to resulting cognitive, behavioral, and motor performance outcomes in probands with de novo CNVs.
DESIGN, SETTING, AND PARTICIPANTS: Family-based study design with a volunteer sample of 56 individuals with de novo 16p11.2 deletions and their noncarrier parents and siblings from the Simons Variation in Individuals Project.
MAIN OUTCOMES AND MEASURES: We used linear mixed-model analysis to measure effect size and intraclass correlation to determine the influence of family background for a de novo CNV on quantitative traits representing the following 3 neurodevelopmental domains: cognitive ability (Full-Scale IQ), social behavior (Social Responsiveness Scale), and neuromotor performance (Purdue Pegboard Test). We included an anthropometric trait, body mass index, for comparison.
RESULTS: A significant deleterious effect of the 16p11.2 deletion was demonstrated across all domains. Relative to the biparental mean, the effect sizes were -1.7 SD for cognitive ability, 2.2 SD for social behavior, and -1.3 SD for neuromotor performance (P < .001). Despite large deleterious effects, significant positive correlations between parents and probands were preserved for the Full-Scale IQ (0.42 [P = .03]), the verbal IQ (0.53 [P = .004]), and the Social Responsiveness Scale (0.52 [P = .009]) scores. We also observed a 1-SD increase in the body mass index of probands compared with siblings, with an intraclass correlation of 0.40 (P = .07).
CONCLUSIONS AND RELEVANCE: Analysis of families with de novo CNVs provides the least confounded estimate of the effect size of the 16p11.2 deletion on heritable, quantitative traits and demonstrates a 1- to 2-SD effect across all neurodevelopmental dimensions. Significant parent-proband correlations indicate that family background contributes to the phenotypic variability seen in this and perhaps other CNV disorders and may have implications for counseling families regarding their children's developmental and psychiatric prognoses. Use of biparental mean scores rather than general population mean scores may be more relevant to examine the effect of a mutation or any other cause of trait variation on a neurodevelopmental outcome and possibly on systems of diagnosis and trait ascertainment for developmental disorders.

PMID: 25493922 [PubMed - indexed for MEDLINE]

Quantifying the effects of rare variants in pedigrees: how far does the apple fall from the tree?

March 25, 2015 - 6:21am
Related Articles

Quantifying the effects of rare variants in pedigrees: how far does the apple fall from the tree?

JAMA Psychiatry. 2015 Feb;72(2):106-7

Authors: Morrow EM

PMID: 25493613 [PubMed - indexed for MEDLINE]

RELN gene polymorphisms and susceptibility to autism in Chinese Han population.

March 25, 2015 - 6:21am
Related Articles

RELN gene polymorphisms and susceptibility to autism in Chinese Han population.

Neurol India. 2012 Nov-Dec;60(6):581-4

Authors: Tian P

Abstract
BACKGROUND: Single nucleotide polymorphisms (SNPs) in the Reelin gene (RELN) are likely candidates to confer risk for autism. The objective of the present study is to investigate the association of RELN gene SNPs with autism.
MATERIALS AND METHODS: A total of 367 Chinese Han subjects were recruited, including 186 autism patients and 181 unrelated healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing methods were used to detect RELN gene polymorphisms. The association between SNPs and autism was analyzed in this study.
RESULTS: The g.333509A>C in intron12 and g.504742G>A in exon60 were detected in the RELN gene and a significant association was found between the g.504742G>A polymorphism and autism. Allele and genotype frequencies for the g.504742G>A polymorphism in autistic patients were significantly different for healthy subjects. There was no significantly difference in g.333509A>C polymorphism and autism in the studied populations.
CONCLUSIONS: Our findings indicated that g.333509A>C was not significantly associated with autism. The g.504742G>A polymorphic variant in the RELN gene might affect subjects susceptibility toward autism in Chinese Han population.

PMID: 23287318 [PubMed - indexed for MEDLINE]

An efficient screening method for simultaneous detection of recurrent copy number variants associated with psychiatric disorders.

March 24, 2015 - 8:17am

An efficient screening method for simultaneous detection of recurrent copy number variants associated with psychiatric disorders.

Clin Chim Acta. 2015 Mar 19;

Authors: Rodriguez-López J, Carrera N, Arrojo M, Amigo J, Sobrino B, Páramo M, Paz E, Agra S, Ramos-Ríos R, Brenlla J, Carracedo Á, Costas J

Abstract
Several recurrent copy number variants (CNV) increasing risk to neuropsychiatric diseases have been identified in recent years. They show variable clinical expressivity, being associated with different disorders, and incomplete penetrance. However, due to its very low frequency, the full variety of clinical outcomes associated with each one of these CNVs is unknown. Current methods for detection of CNVs are labour intensive, expensive or not suitable for high throughput analysis. Quantitative interspecies competitive PCR linked to variant minisequencing and detection by mass-spectrometry may overcome these limitations. Here, we present two multiplex assays based on this method to screen for eleven psychiatric risk CNVs, such as 1q21, 16p11.2, 3q29, or 16p13.11 regions, among others. The assays were tested in our collection of 514 schizophrenia patients. Results were compared with MLPA at two CNVs. Additional positive results were confirmed by exome sequencing. A total of fourteen patients were CNV carriers. The method presents high sensibility and specificity, showing its utility as a cheap, accurate, high throughput screening tool for recurrent CNVs. The method may be very useful for management of psychiatric patients as well as screening of different collections of samples to better identify the full spectrum of clinical variability.

PMID: 25797897 [PubMed - as supplied by publisher]

The GABAA Receptor is an FMRP Target with Therapeutic Potential in Fragile X Syndrome.

March 20, 2015 - 8:57am

The GABAA Receptor is an FMRP Target with Therapeutic Potential in Fragile X Syndrome.

Cell Cycle. 2015 Mar 19;:0

Authors: Braat S, D'Hulst C, Heulens I, De Rubeis S, Mientjes E, Nelson DL, Willemsen R, Bagni C, Van Dam D, De Deyn PP, Kooy RF

Abstract
Previous research indicates that the GABAAergic system is involved in the pathophysiology of the fragile X syndrome, a frequent form of inherited intellectual disability and associated with autism spectrum disorder. However, the molecular mechanism underlying GABAAergic deficits has remained largely unknown. Here, we demonstrate reduced mRNA expression of GABAA receptor subunits in the cortex and cerebellum of young Fmr1 knockout mice. In addition, we show that the previously reported underexpression of specific subunits of the GABAA receptor can be corrected in YAC transgenic rescue mice, containing the full-length human FMR1 gene in an Fmr1 knockout background. Moreover, we demonstrate that FMRP directly binds several GABAA receptor mRNAs. Finally, positive allosteric modulation of GABAA receptors with the neurosteroid ganaxolone can modulate specific behaviours in Fmr1 knockout mice, emphasizing the therapeutic potential of the receptor.

PMID: 25790165 [PubMed - as supplied by publisher]

Pages