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Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling.

June 15, 2016 - 6:20am
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Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling.

PLoS One. 2015;10(10):e0140638

Authors: Speed HE, Masiulis I, Gibson JR, Powell CM

Abstract
A single, maternally inherited, X-linked point mutation leading to an arginine to cysteine substitution at amino acid 451 (R451C) of Neuroligin 3 (NLGN3R451C) is a likely cause of autism in two brothers. Knockin mice expressing the Nlgn3R451C mutation in place of wild-type Nlgn3 demonstrate increased inhibitory synaptic strength in somatosensory cortex, resulting in an excitatory/inhibitory (E/I) imbalance that is potentially relevant for autism-associated behavioral deficits characteristic of these mice. We have replicated the increase in evoked inhibitory postsynaptic currents (eIPSCs) onto layer II/III cortical pyramidal neurons. We also find that increased frequency of spontaneous mIPSCs in Nlgn3R451C mice occurs in the absence of action potential-driven transmission. This suggests the E/I imbalance is due to changes at the synapse level, as opposed to the network level. Next, we use paired whole-cell recordings in an attempt to identify specific interneuron subtypes affected by the Nlgn3R451C mutation. Curiously, we observe no change in the amplitude of cell-to-cell, unitary IPSCs (uIPSCs) from parvalbumin-positive (PV) or somatostatin-positive (SOM) interneurons onto pyramidal neurons. We also observe no change in the number or density of PV and SOM interneurons in LII/III of somatosensory cortex. This effectively rules out a role for these particular interneurons in the increased inhibitory synaptic transmission, pointing to perhaps alternative interneuron subtypes. Lastly, impaired endocannabinoid signaling has been implicated in hippocampal synaptic dysfunction in Nlgn3R451C mice, but has not been investigated at cortical synapses. We find that bath application of the CB1 antagonist, AM 251 in WT mice eliminates the Nlgn3R451C increase in eIPSC amplitude and mIPSC frequency, indicating that increased inhibitory transmission in mutant mice is due, at least in part, to a loss of endocannabinoid signaling through CB1 receptors likely acting at interneurons other than PV or SOM.

PMID: 26469287 [PubMed - indexed for MEDLINE]

Comparison of Fecal Microbiota in Children with Autism Spectrum Disorders and Neurotypical Siblings in the Simons Simplex Collection.

June 15, 2016 - 6:20am
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Comparison of Fecal Microbiota in Children with Autism Spectrum Disorders and Neurotypical Siblings in the Simons Simplex Collection.

PLoS One. 2015;10(10):e0137725

Authors: Son JS, Zheng LJ, Rowehl LM, Tian X, Zhang Y, Zhu W, Litcher-Kelly L, Gadow KD, Gathungu G, Robertson CE, Ir D, Frank DN, Li E

Abstract
In order to assess potential associations between autism spectrum disorder (ASD) phenotype, functional GI disorders and fecal microbiota, we recruited simplex families, which had only a single ASD proband and neurotypical (NT) siblings, through the Simons Simplex Community at the Interactive Autism Network (SSC@IAN). Fecal samples and metadata related to functional GI disorders and diet were collected from ASD probands and NT siblings of ASD probands (age 7-14). Functional gastrointestinal disorders (FGID) were assessed using the parent-completed ROME III questionnaire for pediatric FGIDs, and problem behaviors were assessed using the Child Behavior Check List (CBCL). Targeted quantitative polymerase chain reaction (qPCR) assays were conducted on selected taxa implicated in ASD, including Sutterella spp., Bacteroidetes spp. and Prevotella spp. Illumina sequencing of the V1V2 and the V1V3 regions of the bacterial 16S rRNA genes from fecal DNA was performed to an average depth of 208,000 and 107,000 high-quality reads respectively. Twenty-five of 59 ASD children and 13 of 44 NT siblings met ROME III criteria for at least one FGID. Functional constipation was more prevalent in ASD (17 of 59) compared to NT siblings (6 of 44, P = 0.035). The mean CBCL scores in NT siblings with FGID, ASD children with FGID and ASD without FGID were comparably higher (58-62 vs. 44, P < 0.0001) when compared to NT children without FGID. There was no significant difference in macronutrient intake between ASD and NT siblings. There was no significant difference in ASD severity scores between ASD children with and without FGID. No significant difference in diversity or overall microbial composition was detected between ASD children with NT siblings. Exploratory analysis of the 16S rRNA sequencing data, however, identified several low abundance taxa binned at the genus level that were associated with ASD and/or first order ASD*FGID interactions (FDR <0.1).

PMID: 26427004 [PubMed - indexed for MEDLINE]

Genome-Wide Association Study for Autism Spectrum Disorder in Taiwanese Han Population.

June 15, 2016 - 6:20am
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Genome-Wide Association Study for Autism Spectrum Disorder in Taiwanese Han Population.

PLoS One. 2015;10(9):e0138695

Authors: Kuo PH, Chuang LC, Su MH, Chen CH, Chen CH, Wu JY, Yen CJ, Wu YY, Liu SK, Chou MC, Chou WJ, Chiu YN, Tsai WC, Gau SS

Abstract
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic components. Several recent genome-wide association (GWA) studies in Caucasian samples have reported a number of gene regions and loci correlated with the risk of ASD--albeit with very little consensus across studies.
METHODS: A two-stage GWA study was employed to identify common genetic variants for ASD in the Taiwanese Han population. The discovery stage included 315 patients with ASD and 1,115 healthy controls, using the Affymetrix SNP array 6.0 platform for genotyping. Several gene regions were then selected for fine-mapping and top markers were examined in extended samples. Single marker, haplotype, gene-based, and pathway analyses were conducted for associations.
RESULTS: Seven SNPs had p-values ranging from 3.4~9.9*10-6, but none reached the genome-wide significant level. Five of them were mapped to three known genes (OR2M4, STYK1, and MNT) with significant empirical gene-based p-values in OR2M4 (p = 3.4*10(-5)) and MNT (p = 0.0008). Results of the fine-mapping study showed single-marker associations in the GLIS1 (rs12082358 and rs12080993) and NAALADL2 (rs3914502 and rs2222447) genes, and gene-based associations for the OR2M3-OR2T5 (olfactory receptor genes, p = 0.02), and GLIPR1/KRR1 gene regions (p = 0.015). Pathway analyses revealed important pathways for ASD, such as olfactory and G protein-coupled receptors signaling pathways.
CONCLUSIONS: We reported Taiwanese Han specific susceptibility genes and variants for ASD. However, further replication in other Asian populations is warranted to validate our findings. Investigation in the biological functions of our reported genetic variants might also allow for better understanding on the underlying pathogenesis of autism.

PMID: 26398136 [PubMed - indexed for MEDLINE]

PBAP: a pipeline for file processing and quality control of pedigree data with dense genetic markers.

June 15, 2016 - 6:20am
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PBAP: a pipeline for file processing and quality control of pedigree data with dense genetic markers.

Bioinformatics. 2015 Dec 1;31(23):3790-8

Authors: Nato AQ, Chapman NH, Sohi HK, Nguyen HD, Brkanac Z, Wijsman EM

Abstract
MOTIVATION: Huge genetic datasets with dense marker panels are now common. With the availability of sequence data and recognition of importance of rare variants, smaller studies based on pedigrees are again also common. Pedigree-based samples often start with a dense marker panel, a subset of which may be used for linkage analysis to reduce computational burden and to limit linkage disequilibrium between single-nucleotide polymorphisms (SNPs). Programs attempting to select markers for linkage panels exist but lack flexibility.
RESULTS: We developed a pedigree-based analysis pipeline (PBAP) suite of programs geared towards SNPs and sequence data. PBAP performs quality control, marker selection and file preparation. PBAP sets up files for MORGAN, which can handle analyses for small and large pedigrees, typically human, and results can be used with other programs and for downstream analyses. We evaluate and illustrate its features with two real datasets.
AVAILABILITY AND IMPLEMENTATION: PBAP scripts may be downloaded from http://faculty.washington.edu/wijsman/software.shtml.
CONTACT: wijsman@uw.edu.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 26231429 [PubMed - indexed for MEDLINE]

Behavioral characteristics associated with 19p13.2 microdeletions.

June 15, 2016 - 6:20am
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Behavioral characteristics associated with 19p13.2 microdeletions.

Am J Med Genet A. 2015 Oct;167A(10):2334-43

Authors: Welham A, Barth B, Moss J, Penhallow J, Sheth K, Wilde L, Wynn S, Oliver C

Abstract
A small number of recent papers have described individuals with intellectual disabilities and microdeletions in chromosome band 19p13.2. However, little is known about the behavioral characteristics of individuals with microdeletions in this area. The current study examines behavioral characteristics of a series of 10 participants ranging in age from 2 to 20 years with 19p13.2 microdeletions. Parents/caregivers completed a series of established behavioral measures which have aided the elucidation of the behavioral phenotypes of a number of genetic neurodevelopmental syndromes. All but the youngest two participants (aged 2 and 3 years) were verbal, ambulant, and classified as "partly able" or "able" with regard to self-help skills. Six of eight participants for whom a screening measure for autism spectrum disorders (ASD) could be deployed met criteria for an ASD. Six of the 10 participants had displayed self-injurious behavior in the month prior to assessment, eight had displayed destruction/disruption of property, and eight had shown physically aggressive behaviors. Repetitive behaviors were prevalent in the sample (with all participants displaying at least one repetitive behavior to a clinically relevant level), as were problems with sleep. Low mood was not prevalent in this group, and nor were overactivity or impulsivity. Full determination of a behavioral phenotype for this group would require a larger sample size, distinguishing between genetic subtypes. However, the current data suggest that ASD characteristics, repetitive, and challenging behaviors (such as aggression and self-injury) might be associated with 19p13.2 microdeletions, providing a basis for future investigation.

PMID: 26189583 [PubMed - indexed for MEDLINE]

VoICE: A semi-automated pipeline for standardizing vocal analysis across models.

June 15, 2016 - 6:20am
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VoICE: A semi-automated pipeline for standardizing vocal analysis across models.

Sci Rep. 2015;5:10237

Authors: Burkett ZD, Day NF, Peñagarikano O, Geschwind DH, White SA

Abstract
The study of vocal communication in animal models provides key insight to the neurogenetic basis for speech and communication disorders. Current methods for vocal analysis suffer from a lack of standardization, creating ambiguity in cross-laboratory and cross-species comparisons. Here, we present VoICE (Vocal Inventory Clustering Engine), an approach to grouping vocal elements by creating a high dimensionality dataset through scoring spectral similarity between all vocalizations within a recording session. This dataset is then subjected to hierarchical clustering, generating a dendrogram that is pruned into meaningful vocalization "types" by an automated algorithm. When applied to birdsong, a key model for vocal learning, VoICE captures the known deterioration in acoustic properties that follows deafening, including altered sequencing. In a mammalian neurodevelopmental model, we uncover a reduced vocal repertoire of mice lacking the autism susceptibility gene, Cntnap2. VoICE will be useful to the scientific community as it can standardize vocalization analyses across species and laboratories.

PMID: 26018425 [PubMed - indexed for MEDLINE]

Genetic Mapping in Mice Reveals the Involvement of Pcdh9 in Long-Term Social and Object Recognition and Sensorimotor Development.

June 15, 2016 - 6:20am
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Genetic Mapping in Mice Reveals the Involvement of Pcdh9 in Long-Term Social and Object Recognition and Sensorimotor Development.

Biol Psychiatry. 2015 Oct 1;78(7):485-95

Authors: Bruining H, Matsui A, Oguro-Ando A, Kahn RS, Van't Spijker HM, Akkermans G, Stiedl O, van Engeland H, Koopmans B, van Lith HA, Oppelaar H, Tieland L, Nonkes LJ, Yagi T, Kaneko R, Burbach JP, Yamamoto N, Kas MJ

Abstract
BACKGROUND: Quantitative genetic analysis of basic mouse behaviors is a powerful tool to identify novel genetic phenotypes contributing to neurobehavioral disorders. Here, we analyzed genetic contributions to single-trial, long-term social and nonsocial recognition and subsequently studied the functional impact of an identified candidate gene on behavioral development.
METHODS: Genetic mapping of single-trial social recognition was performed in chromosome substitution strains, a sophisticated tool for detecting quantitative trait loci (QTL) of complex traits. Follow-up occurred by generating and testing knockout (KO) mice of a selected QTL candidate gene. Functional characterization of these mice was performed through behavioral and neurological assessments across developmental stages and analyses of gene expression and brain morphology.
RESULTS: Chromosome substitution strain 14 mapping studies revealed an overlapping QTL related to long-term social and object recognition harboring Pcdh9, a cell-adhesion gene previously associated with autism spectrum disorder. Specific long-term social and object recognition deficits were confirmed in homozygous (KO) Pcdh9-deficient mice, while heterozygous mice only showed long-term social recognition impairment. The recognition deficits in KO mice were not associated with alterations in perception, multi-trial discrimination learning, sociability, behavioral flexibility, or fear memory. Rather, KO mice showed additional impairments in sensorimotor development reflected by early touch-evoked biting, rotarod performance, and sensory gating deficits. This profile emerged with structural changes in deep layers of sensory cortices, where Pcdh9 is selectively expressed.
CONCLUSIONS: This behavior-to-gene study implicates Pcdh9 in cognitive functions required for long-term social and nonsocial recognition. This role is supported by the involvement of Pcdh9 in sensory cortex development and sensorimotor phenotypes.

PMID: 25802080 [PubMed - indexed for MEDLINE]

Executive functioning in autism spectrum disorders: influence of task and sample characteristics and relation to symptom severity.

June 15, 2016 - 6:20am
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Executive functioning in autism spectrum disorders: influence of task and sample characteristics and relation to symptom severity.

Eur Child Adolesc Psychiatry. 2015 Nov;24(11):1399-417

Authors: Van Eylen L, Boets B, Steyaert J, Wagemans J, Noens I

Abstract
Impaired executive functioning (EF) has been proposed to underlie symptoms of autism spectrum disorders (ASD). However, insight in the EF profile of ASD individuals is hampered due to task impurity and inconsistent findings. To elucidate these inconsistencies, we investigated the influence of task and sample characteristics on EF in ASD, with an extended test battery designed to reduce task impurity. Additionally, we studied the relation between EF and ASD symptoms. EF (inhibition, cognitive flexibility, generativity, working memory and planning) was measured in open-ended versus structured assessment situations, while controlling for possible confounding EF and non-EF variables. The performance of 50 individuals with ASD was compared with that of 50 age, gender and IQ matched typically developing (TD) individuals. The effects of group (ASD versus TD), age (children versus adolescents) and gender were examined, as well as the correlation between age, IQ, ASD symptoms and EF. Individuals with ASD showed impairments in all EF domains, but deficits were more pronounced in open-ended compared to structured settings. Group differences did not depend on gender and only occasionally on participants' age. This suggests that inconsistencies between studies largely result from differences in task characteristics and less from differences in the investigated sample features. However, age and IQ strongly correlated with EF, indicating that group differences in these factors should be controlled for when studying EF. Finally, EF correlated with both social and non-social ASD symptoms, but further research is needed to clarify the nature of this relationship.

PMID: 25697266 [PubMed - indexed for MEDLINE]

Obsessive-Compulsive Disorder and Autism Spectrum Disorders: Longitudinal and Offspring Risk.

June 14, 2016 - 9:17am
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Obsessive-Compulsive Disorder and Autism Spectrum Disorders: Longitudinal and Offspring Risk.

PLoS One. 2015;10(11):e0141703

Authors: Meier SM, Petersen L, Schendel DE, Mattheisen M, Mortensen PB, Mors O

Abstract
BACKGROUND: Despite substantial similarities and overlaps in the pathophysiology of obsessive-compulsive disorders (OCD) and autism spectrum disorders, little is known about the clinical and etiologic cohesion of these two disorders. We therefore aimed to determine the patterns of comorbidity, longitudinal risks, and shared familial risks between these disorders.
METHODS: In a prospective study design we explored the effect of a prior diagnosis of OCD in patients and parents on the susceptibility to autism spectrum disorders and vice versa. Analyses were adjusted for sex, age, calendar year, parental age and place at residence at time of birth. As measures of relative risk incidence rate ratios (IRR) and accompanying 95% confidence intervals (CIs) were employed.
RESULTS: The risk of a comorbid diagnosis of OCD in individuals with autism spectrum disorder and aggregation of autism spectrum disorders in offspring of parents with OCD were increased. Individuals first diagnosed with autism spectrum disorders had a 2-fold higher risk of a later diagnosis of OCD (IRR = 2.18, 95% CI = 1.91-2.48), whereas individuals diagnosed with OCD displayed a nearly 4-fold higher risk to be diagnosed with autism spectrum disorders (IRR = 3.91, 95% CI = 3.46-4.40) later in life. The observed associations were somewhat stronger for less severe types of autism spectrum disorders without a comorbid diagnosis of mental disabilities.
CONCLUSIONS: The high comorbidity, sequential risk, and shared familial risks between OCD and autism spectrum disorders are suggestive of partially shared etiological mechanisms. The results have implications for current gene-searching efforts and for clinical practice.

PMID: 26558765 [PubMed - indexed for MEDLINE]

17p11.2 and Xq28 duplication detected in a girl diagnosed with Potocki-Lupski syndrome.

June 14, 2016 - 9:17am
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17p11.2 and Xq28 duplication detected in a girl diagnosed with Potocki-Lupski syndrome.

BMC Res Notes. 2015;8:506

Authors: Sumathipala DS, Mandawala EN, Sumanasena SP, Dissanayake VH

Abstract
BACKGROUND: Potocki-Lupski syndrome is a microduplication syndrome associated with duplication at 17p11.2. Features include facial dysmorphism, moderate to mild cognitive impairment and behavioural abnormalities including autism spectrum disorders.
CASE PRESENTATION: We describe a patient from Sri Lanka that was referred for genetic assessment at 4 years of age due to subtle facial dysmorphism and expressive language impairment. She was diagnosed with Potocki-Lupski syndrome through multiplex ligation probe amplification. She carried two duplications; one in 17p11.2 consistent with Potocki-Lupski, and one in Xq including the region for X-linked intellectual disability.
CONCLUSION: Despite the absence of expected behavioural symptoms, many features of this patient are in accordance with Potocki-Lupski syndrome. This is the first diagnosed patient in Sri Lanka.

PMID: 26419729 [PubMed - indexed for MEDLINE]

Mutations in ARID2 are associated with intellectual disabilities.

June 14, 2016 - 9:17am
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Mutations in ARID2 are associated with intellectual disabilities.

Neurogenetics. 2015 Oct;16(4):307-14

Authors: Shang L, Cho MT, Retterer K, Folk L, Humberson J, Rohena L, Sidhu A, Saliganan S, Iglesias A, Vitazka P, Juusola J, O'Donnell-Luria AH, Shen Y, Chung WK

Abstract
The etiology of intellectual disabilities (ID) remains unknown for the majority of patients. Due to reduced reproductive fitness in many individuals with ID, de novo mutations account for a significant portion of severe ID. The ATP-dependent SWI/SNF chromatin modifier has been linked with neurodevelopmental disorders including ID and autism. ARID2 is an intrinsic component of polybromo-associated BAF (PBAF), the SWI/SNF subcomplex. In this study, we used clinical whole exome sequencing (WES) in proband-parent-trios to identify the etiology of ID. We identified four independent, novel, loss of function variants in ARID2 gene in four patients, three of which were confirmed to be de novo. The patients all have ID and share other clinical characteristics including attention deficit hyperactivity disorder, short stature, dysmorphic facial features, and Wormian bones. All four novel variants are predicted to lead to a premature termination with the loss of the two conservative zinc finger motifs. This is the first report of mutations in ARID2 associated with developmental delay and ID.

PMID: 26238514 [PubMed - indexed for MEDLINE]

Current knowledge on the genetics of autism and propositions for future research.

June 13, 2016 - 6:07am

Current knowledge on the genetics of autism and propositions for future research.

C R Biol. 2016 Jun 8;

Authors: Bourgeron T

Abstract
Autism spectrum disorders (ASD) are a heterogeneous group of neuropsychiatric disorders characterized by problems in social communication, as well as by the presence of restricted interests, stereotyped and repetitive behaviours. In the last 40years, genetic studies have provided crucial information on the causes of ASD and its diversity. In this article, I will first review the current knowledge on the genetics of ASD and then suggest three propositions to foster research in this field. Twin and familial studies estimated the heritability of ASD to be 50%. While most of the inherited part of ASD is captured by common variants, our current knowledge on the genetics of ASD comes almost exclusively from the identification of highly penetrant de novo mutations through candidate gene or whole exome/genome sequencing studies. Approximately 10% of patients with ASD, especially those with intellectual disability, are carriers of de novo copy-number (CNV) or single nucleotide variants (SNV) affecting clinically relevant genes for ASD. Given the function of these genes, it was hypothesized that abnormal synaptic plasticity and failure of neuronal/synaptic homeostasis could increase the risk of ASD. In addition to these discoveries, three propositions coming from institutions, researchers and/or communities of patients and families can be made to foster research on ASD: (i) to use more dimensional and quantitative data than diagnostic categories; (ii) to increase data sharing and research on genetic and brain diversity in human populations; (iii) to involve patients and relatives as participants for research. Hopefully, this knowledge will lead to a better diagnosis, care and integration of individuals with ASD.

PMID: 27289453 [PubMed - as supplied by publisher]

Autism spectrum disorder prevalence and proximity to industrial facilities releasing arsenic, lead or mercury.

June 11, 2016 - 6:03am
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Autism spectrum disorder prevalence and proximity to industrial facilities releasing arsenic, lead or mercury.

Sci Total Environ. 2015 Dec 1;536:245-51

Authors: Dickerson AS, Rahbar MH, Han I, Bakian AV, Bilder DA, Harrington RA, Pettygrove S, Durkin M, Kirby RS, Wingate MS, Tian LH, Zahorodny WM, Pearson DA, Moyé LA, Baio J

Abstract
Prenatal and perinatal exposures to air pollutants have been shown to adversely affect birth outcomes in offspring and may contribute to prevalence of autism spectrum disorder (ASD). For this ecologic study, we evaluated the association between ASD prevalence, at the census tract level, and proximity of tract centroids to the closest industrial facilities releasing arsenic, lead or mercury during the 1990s. We used 2000 to 2008 surveillance data from five sites of the Autism and Developmental Disabilities Monitoring (ADDM) network and 2000 census data to estimate prevalence. Multi-level negative binomial regression models were used to test associations between ASD prevalence and proximity to industrial facilities in existence from 1991 to 1999 according to the US Environmental Protection Agency Toxics Release Inventory (USEPA-TRI). Data for 2489 census tracts showed that after adjustment for demographic and socio-economic area-based characteristics, ASD prevalence was higher in census tracts located in the closest 10th percentile compared of distance to those in the furthest 50th percentile (adjusted RR=1.27, 95% CI: (1.00, 1.61), P=0.049). The findings observed in this study are suggestive of the association between urban residential proximity to industrial facilities emitting air pollutants and higher ASD prevalence.

PMID: 26218563 [PubMed - indexed for MEDLINE]

Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca(2+)-dependent inactivation.

June 10, 2016 - 9:01am
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Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca(2+)-dependent inactivation.

Nat Commun. 2016;7:10370

Authors: Dick IE, Joshi-Mukherjee R, Yang W, Yue DT

Abstract
Timothy Syndrome (TS) is a multisystem disorder, prominently featuring cardiac action potential prolongation with paroxysms of life-threatening arrhythmias. The underlying defect is a single de novo missense mutation in CaV1.2 channels, either G406R or G402S. Notably, these mutations are often viewed as equivalent, as they produce comparable defects in voltage-dependent inactivation and cause similar manifestations in patients. Yet, their effects on calcium-dependent inactivation (CDI) have remained uncertain. Here, we find a significant defect in CDI in TS channels, and uncover a remarkable divergence in the underlying mechanism for G406R versus G402S variants. Moreover, expression of these TS channels in cultured adult guinea pig myocytes, combined with a quantitative ventricular myocyte model, reveals a threshold behaviour in the induction of arrhythmias due to TS channel expression, suggesting an important therapeutic principle: a small shift in the complement of mutant versus wild-type channels may confer significant clinical improvement.

PMID: 26822303 [PubMed - indexed for MEDLINE]

Autism Spectrum Disorders: Translating human deficits into mouse behavior.

June 10, 2016 - 9:01am
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Autism Spectrum Disorders: Translating human deficits into mouse behavior.

Neurobiol Learn Mem. 2015 Oct;124:71-87

Authors: Pasciuto E, Borrie SC, Kanellopoulos AK, Santos AR, Cappuyns E, D'Andrea L, Pacini L, Bagni C

Abstract
Autism Spectrum Disorders are a heterogeneous group of neurodevelopmental disorders, with rising incidence but little effective therapeutic intervention available. Currently two main clinical features are described to diagnose ASDs: impaired social interaction and communication, and repetitive behaviors. Much work has focused on understanding underlying causes of ASD by generating animal models of the disease, in the hope of discovering signaling pathways and cellular targets for drug intervention. Here we review how ASD behavioral phenotypes can be modeled in the mouse, the most common animal model currently in use in this field, and discuss examples of genetic mouse models of ASD with behavioral features that recapitulate various symptoms of ASD.

PMID: 26220900 [PubMed - indexed for MEDLINE]

Genomic Imprinting.

June 9, 2016 - 5:51pm

Genomic Imprinting.

Open Access Maced J Med Sci. 2016 Mar 15;4(1):181-184

Authors: Bajrami E, Spiroski M

Abstract
BACKGROUND: Genomic imprinting is the inheritance out of Mendelian borders. Many of inherited diseases and human development violates Mendelian law of inheritance, this way of inheriting is studied by epigenetics.
AIM: The aim of this review is to analyze current opinions and options regarding to this way of inheriting.
RESULTS: Epigenetics shows that gene expression undergoes changes more complex than modifications in the DNA sequence; it includes the environmental influence on the gametes before conception. Humans inherit two alleles from mother and father, both are functional for the majority of the genes, but sometimes one is turned off or "stamped" and doesn't show in offspring, that gene is imprinted. Imprinting means that that gene is silenced, and gene from other parent is expressed. The mechanisms for imprinting are still incompletely defined, but they involve epigenetic modifications that are erased and then reset during the creation of eggs and sperm. Genomic imprinting is a process of silencing genes through DNA methylation. The repressed allele is methylated, while the active allele is unmethylated. The most well-known conditions include Prader-Willi syndrome, and Angelman syndrome. Both of these syndromes can be caused by imprinting or other errors involving genes on the long arm of chromosome 15.
CONCLUSIONS: Genomic imprinting and other epigenetic mechanisms such as environment is shown that plays role in offspring neurodevelopment and autism spectrum disorder.

PMID: 27275355 [PubMed - as supplied by publisher]

Diagnostic yield of array CGH in patients with autism spectrum disorder in Hong Kong.

June 9, 2016 - 5:51pm

Diagnostic yield of array CGH in patients with autism spectrum disorder in Hong Kong.

Clin Transl Med. 2016 Dec;5(1):18

Authors: Siu WK, Lam CW, Mak CM, Lau ET, Tang MH, Tang WF, Poon-Mak RS, Lee CC, Hung SF, Leung PW, Kwong KL, Yau EK, Ng GS, Fong NC, Chan KY

Abstract
BACKGROUND: Chromosomal microarray offers superior sensitivity for identification of submicroscopic copy number variants (CNV) and it is advocated to be the first tier genetic testing for patients with autism spectrum disorder (ASD). In this regard, diagnostic yield of array comparative genomic hybridization (CGH) for ASD patients is determined in a cohort of Chinese patients in Hong Kong.
METHODS: A combined adult and paediatric cohort of 68 Chinese ASD patients (41 patients in adult group and 27 patients in paediatric group). The genomic DNA extracted from blood samples were analysed by array CGH using NimbleGen CGX-135K oligonucleotide array.
RESULTS: We identified 15 CNV and eight of them were clinically significant. The overall diagnostic yield was 11.8 %. Five clinically significant CNV were detected in the adult group and three were in the paediatric group, providing diagnostic yields of 12.2 and 11.1 % respectively. The most frequently detected CNV was 16p13.11 duplications which were present in 4 patients (5.9 % of the cohort).
CONCLUSIONS: In this study, a satisfactory diagnostic yield of array CGH was demonstrated in a Chinese ASD patient cohort which supported the clinical usefulness of array CGH as the first line testing of ASD in Hong Kong.

PMID: 27271878 [PubMed - as supplied by publisher]

Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons.

June 9, 2016 - 5:51pm
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Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons.

Science. 2016 May 6;352(6286):aaf2669

Authors: Yi F, Danko T, Botelho SC, Patzke C, Pak C, Wernig M, Südhof TC

Abstract
Heterozygous SHANK3 mutations are associated with idiopathic autism and Phelan-McDermid syndrome. SHANK3 is a ubiquitously expressed scaffolding protein that is enriched in postsynaptic excitatory synapses. Here, we used engineered conditional mutations in human neurons and found that heterozygous and homozygous SHANK3 mutations severely and specifically impaired hyperpolarization-activated cation (Ih) channels. SHANK3 mutations caused alterations in neuronal morphology and synaptic connectivity; chronic pharmacological blockage of Ih channels reproduced these phenotypes, suggesting that they may be secondary to Ih-channel impairment. Moreover, mouse Shank3-deficient neurons also exhibited severe decreases in Ih currents. SHANK3 protein interacted with hyperpolarization-activated cyclic nucleotide-gated channel proteins (HCN proteins) that form Ih channels, indicating that SHANK3 functions to organize HCN channels. Our data suggest that SHANK3 mutations predispose to autism, at least partially, by inducing an Ih channelopathy that may be amenable to pharmacological intervention.

PMID: 26966193 [PubMed - indexed for MEDLINE]

Identification of Males with Cryptic Fragile X Alleles by Methylation-Specific Quantitative Melt Analysis.

June 9, 2016 - 5:51pm
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Identification of Males with Cryptic Fragile X Alleles by Methylation-Specific Quantitative Melt Analysis.

Clin Chem. 2016 Feb;62(2):343-52

Authors: Aliaga SM, Slater HR, Francis D, Du Sart D, Li X, Amor DJ, Alliende AM, Santa Maria L, Faundes V, Morales P, Trigo C, Salas I, Curotto B, Godler DE

Abstract
BACKGROUND: FMR1 full mutations (FMs) (CGG expansion >200) in males mosaic for a normal (<45 CGG) or gray-zone (GZ) (45-54 CGG) allele can be missed with the standard 2-step fragile X syndrome (FXS) testing protocols, largely because the first-line PCR tests showing a normal or GZ allele are not reflexed to the second-line test that can detect FM.
METHODS: We used methylation-specific quantitative melt analysis (MS-QMA) to determine the prevalence of cryptic FM alleles in 2 independent cohorts of male patients (994 from Chile and 2392 from Australia) referred for FXS testing from 2006 to 2013. All MS-QMA-positive cases were retested with commercial triplet primed PCR, methylation-sensitive Southern blot, and a methylation-specific EpiTYPER-based test.
RESULTS: All 38 FMs detected with the standard 2-step protocol were detected with MS-QMA. However, MS-QMA identified methylation mosaicism in an additional 15% and 11% of patients in the Chilean and Australian cohorts, respectively, suggesting the presence of a cryptic FM. Of these additional patients, 57% were confirmed to carry cryptic expanded alleles in blood, buccal mucosa, or saliva samples. Further confirmation was provided by identifying premutation (CGG 55-199) alleles in mothers of probands with methylation-sensitive Southern blot. Neurocognitive assessments showed that low-level mosaicism for cryptic FM alleles was associated with cognitive impairment or autism.
CONCLUSIONS: A substantial number of mosaic FM males who have cognitive impairment or autism are not diagnosed with the currently recommended 2-step testing protocol and can be identified with MS-QMA as a first-line test.

PMID: 26715660 [PubMed - indexed for MEDLINE]

Peroxisomes in brain development and function.

June 9, 2016 - 5:51pm
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Peroxisomes in brain development and function.

Biochim Biophys Acta. 2016 May;1863(5):934-55

Authors: Berger J, Dorninger F, Forss-Petter S, Kunze M

Abstract
Peroxisomes contain numerous enzymatic activities that are important for mammalian physiology. Patients lacking either all peroxisomal functions or a single enzyme or transporter function typically develop severe neurological deficits, which originate from aberrant development of the brain, demyelination and loss of axonal integrity, neuroinflammation or other neurodegenerative processes. Whilst correlating peroxisomal properties with a compilation of pathologies observed in human patients and mouse models lacking all or individual peroxisomal functions, we discuss the importance of peroxisomal metabolites and tissue- and cell type-specific contributions to the observed brain pathologies. This enables us to deconstruct the local and systemic contribution of individual metabolic pathways to specific brain functions. We also review the recently discovered variability of pathological symptoms in cases with unexpectedly mild presentation of peroxisome biogenesis disorders. Finally, we explore the emerging evidence linking peroxisomes to more common neurological disorders such as Alzheimer's disease, autism and amyotrophic lateral sclerosis.

PMID: 26686055 [PubMed - indexed for MEDLINE]

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