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Prevalence, comorbidity and heritability of hoarding symptoms in adolescence: a population based twin study in 15-year olds.

April 1, 2014 - 7:50am
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Prevalence, comorbidity and heritability of hoarding symptoms in adolescence: a population based twin study in 15-year olds.

PLoS One. 2013;8(7):e69140

Authors: Ivanov VZ, Mataix-Cols D, Serlachius E, Lichtenstein P, Anckarsäter H, Chang Z, Gumpert CH, Lundström S, Långström N, Rück C

Abstract
BACKGROUND: Hoarding Disorder (HD) is often assumed to be an 'old age' problem, but many individuals diagnosed with HD retrospectively report first experiencing symptoms in childhood or adolescence. We examined the prevalence, comorbidity and etiology of hoarding symptoms in adolescence.
METHODS: To determine the presence of clinically significant hoarding symptoms, a population-based sample of 15-year old twins (N = 3,974) completed the Hoarding Rating Scale-Self Report. Co-occurring Obsessive Compulsive Disorder (OCD), Autism Spectrum Disorders (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) were estimated from parental report. Model-fitting analyses divided hoarding symptom scores into additive genetic, shared, and non-shared environmental effects.
RESULTS: The prevalence of clinically significant hoarding symptoms was 2% (95% CI 1.6-2.5%), with a significantly higher prevalence in girls than boys. Exclusion of the clutter criterion (as adolescents do not have control over their environment) increased the prevalence rate to 3.7% (95% CI 3.1-4.3%). Excessive acquisition was reported by 30-40% among those with clinically significant hoarding symptoms. The prevalence of co-occurring OCD (2.9%), ASD (2.9%) and ADHD (10.0%) was comparable in hoarding and non-hoarding teenagers. Model-fitting analyses suggested that, in boys, additive genetic (32%; 95% CI 13-44%) and non-shared environmental effects accounted for most of the variance. In contrast, among girls, shared and non-shared environmental effects explained most of the variance, while additive genetic factors played a negligible role.
CONCLUSIONS: Hoarding symptoms are relatively prevalent in adolescents, particularly in girls, and cause distress and/or impairment. Hoarding was rarely associated with other common neurodevelopmental disorders, supporting its DSM-5 status as an independent diagnosis. The relative importance of genetic and shared environmental factors for hoarding differed across sexes. The findings are suggestive of dynamic developmental genetic and environmental effects operating from adolescence onto adulthood.

PMID: 23874893 [PubMed - indexed for MEDLINE]

Genetic Risk for Attention-Deficit/Hyperactivity Disorder Contributes to Neurodevelopmental Traits in the General Population.

March 29, 2014 - 8:25am

Genetic Risk for Attention-Deficit/Hyperactivity Disorder Contributes to Neurodevelopmental Traits in the General Population.

Biol Psychiatry. 2014 Feb 25;

Authors: Martin J, Hamshere ML, Stergiakouli E, O'Donovan MC, Thapar A

Abstract
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) can be viewed as the extreme end of traits in the general population. Epidemiological and twin studies suggest that ADHD frequently co-occurs with and shares genetic susceptibility with autism spectrum disorder (ASD) and ASD-related traits. The aims of this study were to determine whether a composite of common molecular genetic variants, previously found to be associated with clinically diagnosed ADHD, predicts ADHD and ASD-related traits in the general population.
METHODS: Polygenic risk scores were calculated in the Avon Longitudinal Study of Parents and Children (ALSPAC) population sample (N = 8229) based on a discovery case-control genome-wide association study of childhood ADHD. Regression analyses were used to assess whether polygenic scores predicted ADHD traits and ASD-related measures (pragmatic language abilities and social cognition) in the ALSPAC sample. Polygenic scores were also compared in boys and girls endorsing any (rating ≥1) ADHD item (n = 3623).
RESULTS: Polygenic risk for ADHD showed a positive association with ADHD traits (hyperactive-impulsive, p = .0039; inattentive, p = .037). Polygenic risk for ADHD was also negatively associated with pragmatic language abilities (p = .037) but not with social cognition (p = .43). In children with a rating ≥1 for ADHD traits, girls had a higher polygenic score than boys (p = .003).
CONCLUSIONS: These findings provide molecular genetic evidence that risk alleles for the categorical disorder of ADHD influence hyperactive-impulsive and attentional traits in the general population. The results further suggest that common genetic variation that contributes to ADHD diagnosis may also influence ASD-related traits, which at their extreme are a characteristic feature of ASD.

PMID: 24673882 [PubMed - as supplied by publisher]

Patches of disorganization in the neocortex of children with autism.

March 29, 2014 - 8:25am
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Patches of disorganization in the neocortex of children with autism.

N Engl J Med. 2014 Mar 27;370(13):1209-19

Authors: Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, Wynshaw-Boris A, Colamarino SA, Lein ES, Courchesne E

Abstract
BACKGROUND: Autism involves early brain overgrowth and dysfunction, which is most strongly evident in the prefrontal cortex. As assessed on pathological analysis, an excess of neurons in the prefrontal cortex among children with autism signals a disturbance in prenatal development and may be concomitant with abnormal cell type and laminar development.
METHODS: To systematically examine neocortical architecture during the early years after the onset of autism, we used RNA in situ hybridization with a panel of layer- and cell-type-specific molecular markers to phenotype cortical microstructure. We assayed markers for neurons and glia, along with genes that have been implicated in the risk of autism, in prefrontal, temporal, and occipital neocortical tissue from postmortem samples obtained from children with autism and unaffected children between the ages of 2 and 15 years.
RESULTS: We observed focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in prefrontal and temporal cortical tissue from 10 of 11 children with autism and from 1 of 11 unaffected children. We observed heterogeneity between cases with respect to cell types that were most abnormal in the patches and the layers that were most affected by the pathological features. No cortical layer was uniformly spared, with the clearest signs of abnormal expression in layers 4 and 5. Three-dimensional reconstruction of layer markers confirmed the focal geometry and size of patches.
CONCLUSIONS: In this small, explorative study, we found focal disruption of cortical laminar architecture in the cortexes of a majority of young children with autism. Our data support a probable dysregulation of layer formation and layer-specific neuronal differentiation at prenatal developmental stages. (Funded by the Simons Foundation and others.).

PMID: 24670167 [PubMed - in process]

Establishing a reference group for distal 18q-: clinical description and molecular basis.

March 29, 2014 - 8:25am
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Establishing a reference group for distal 18q-: clinical description and molecular basis.

Hum Genet. 2014 Feb;133(2):199-209

Authors: Cody JD, Hasi M, Soileau B, Heard P, Carter E, Sebold C, O'Donnell L, Perry B, Stratton RF, Hale DE

Abstract
Although constitutional chromosome abnormalities have been recognized since the 1960s, clinical characterization and development of treatment options have been hampered by their obvious genetic complexity and relative rarity. Additionally, deletions of 18q are particularly heterogeneous, with no two people having the same breakpoints. We identified 16 individuals with deletions that, despite unique breakpoints, encompass the same set of genes within a 17.6-Mb region. This group represents the most genotypically similar group yet identified with distal 18q deletions. As the deletion is of average size when compared with other 18q deletions, this group can serve as a reference point for the clinical and molecular description of this condition. We performed a thorough medical record review as well as a series of clinical evaluations on 14 of the 16 individuals. Common functional findings included developmental delays, hypotonia, growth hormone deficiency, and hearing loss. Structural anomalies included foot anomalies, ear canal atresia/stenosis, and hypospadias. The majority of individuals performed within the low normal range of cognitive ability but had more serious deficits in adaptive abilities. Of interest, the hemizygous region contains 38 known genes, 26 of which are sufficiently understood to tentatively determine dosage sensitivity. Published data suggest that 20 are unlikely to cause an abnormal phenotype in the hemizygous state and five are likely to be dosage sensitive: TNX3, NETO1, ZNF407, TSHZ1, and NFATC. A sixth gene, ATP9B, may be conditionally dosage sensitive. Not all distal 18q- phenotypes can be attributed to these six genes; however, this is an important advance in the molecular characterization of 18q deletions.

PMID: 24092497 [PubMed - indexed for MEDLINE]

Cholesterol metabolism deficiency.

March 29, 2014 - 8:25am
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Cholesterol metabolism deficiency.

Handb Clin Neurol. 2013;113:1845-50

Authors: Jira P

Abstract
Genetic defects in enzymes responsible for cholesterol biosynthesis have emerged as important causes of congenital dysmorphology and retardation syndromes. Cholesterol is an important constituent of the cell membrane of most eukaryotic cells, in myelin formation in the brain, spinal cord, and peripheral nervous system, and acts as the precursor for steroid hormones and bile acids. Finally, cholesterol has important interactions with proteins, which control embryonic development. To date, eight distinct inherited disorders have been linked to different defects in cholesterol biosynthesis. Two result from an enzyme defect in the pre-squalene segment of the pathway: the classical form of mevalonic aciduria and the hyperimmunoglobulinemia D syndrome, also known as Dutch-type periodic fever. Six defects in the post-squalene segment of the pathway include: Smith-Lemli-Opitz syndrome, two X-linked dominant inherited and male-lethal disorders, Conradi-Hünermann-Happle syndrome and congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD), and at least three extremely rare autosomal recessive disorders, Greenberg skeletal dysplasia, lathosterolosis, and desmosterolosis. All these inborn errors known to date have been linked to deficiency of specific enzymes on the basis of elevated levels of specific sterol intermediates in tissues of affected patients followed by demonstrating disease-causing mutations in the encoding genes. These cholesterol deficiency multiple malformation-retardation syndromes have clinical overlap. Besides psychomotor retardation, developmental delay, structural brain malformations, multiple congenital anomalies, microcephaly, and cataract, impaired cholesterol biosynthesis is associated with autism and other behavioral disorders.

PMID: 23622407 [PubMed - indexed for MEDLINE]

Creatine deficiency syndromes.

March 29, 2014 - 8:25am
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Creatine deficiency syndromes.

Handb Clin Neurol. 2013;113:1837-43

Authors: Schulze A

Abstract
The lack of creatine in the central nervous system causes a severe but treatable neurological disease. Three inherited defects, AGAT, GAMT, and CrT deficiency, compromising synthesis and transport of creatine have been discovered recently. Together these so-called creatine deficiency syndromes (CDS) might represent the most frequent metabolic disorders with a primarily neurological phenotype. Patients with CDS present with global developmental delays, mental retardation, speech impairment especially affecting active language, seizures, extrapyramidal movement disorder, and autism spectrum disorder. The two defects in the creatine synthesis, AGAT and GAMT, are autosomal recessive disorders. They can be diagnosed by analysis of the creatine, guanidinoacetate, and creatinine in body fluids. Treatment is available and, especially when introduced in infancy, has a good outcome. The defect of creatine transport, CrT, is an X-linked condition and perhaps the most frequent reasons for X-linked mental retardation. Diagnosis is made by an increased ratio of creatine to creatinine in urine, but successful treatment still needs to be explored. CDS are under-diagnosed because easy to miss in standard diagnostic workup. Because CDS represent a frequent cause of cognitive and neurological impairment that is treatable they warrant consideration in the workup for genetic mental retardation syndromes, for intractable seizure disorders, and for neurological diseases with a predominant lack of active speech.

PMID: 23622406 [PubMed - indexed for MEDLINE]

Outfoxed by RBFOX1-A caution about ascertainment bias.

March 26, 2014 - 6:37am

Outfoxed by RBFOX1-A caution about ascertainment bias.

Am J Med Genet A. 2014 Mar 24;

Authors: Kamien B, Lionel AC, Bain N, Scherer SW, Hunter M

Abstract
We report on two patients with intragenic deletions of RBFOX1 and one patient with an intragenic duplication of RBFOX1. These patients, by report, all had autism spectrum disorder and/or developmental delay and had strong family histories of these conditions. We initially hypothesized that RBFOX1 was another susceptibility locus for autism spectrum disorder or developmental delay. However, epidemiological evidence examining large numbers of individuals did not support this hypothesis and the data presented here suggests that RBFOX1 intragenic copy number variants are not pathogenic. This contradicts previous reports that examined smaller numbers of patients and controls. © 2014 Wiley Periodicals, Inc.

PMID: 24664471 [PubMed - as supplied by publisher]

Epigenetic findings in autism: new perspectives for therapy.

March 26, 2014 - 6:37am
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Epigenetic findings in autism: new perspectives for therapy.

Int J Environ Res Public Health. 2013 Sep;10(9):4261-73

Authors: Siniscalco D, Cirillo A, Bradstreet JJ, Antonucci N

Abstract
Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by dysfunctions in social interactions, communications, restricted interests, and repetitive stereotypic behaviors. Despite extensive genetic and biological research, significant controversy surrounds our understanding of the specific mechanisms of their pathogenesis. However, accumulating evidence points to the involvement of epigenetic modifications as foundational in creating ASD pathophysiology. Epigenetic modifications or the alteration of DNA transcription via variations in DNA methylation and histone modifications but without alterations in the DNA sequence, affect gene regulation. These alterations in gene expression, obtained through DNA methylation and/or histone modifications, result from transcriptional regulatory influences of environmental factors, such as nutritional deficiencies, various toxicants, immunological effects, and pharmaceuticals. As such these effects are epigenetic regulators which determine the final biochemistry and physiology of the individual. In contrast to psychopharmacological interventions, bettering our understanding of how these gene-environmental interactions create autistic symptoms should facilitate the development of therapeutic targeting of gene expression for ASD biomedical care.

PMID: 24030655 [PubMed - indexed for MEDLINE]

Comparative RNA editing in autistic and neurotypical cerebella.

March 26, 2014 - 6:37am
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Comparative RNA editing in autistic and neurotypical cerebella.

Mol Psychiatry. 2013 Sep;18(9):1041-8

Authors: Eran A, Li JB, Vatalaro K, McCarthy J, Rahimov F, Collins C, Markianos K, Margulies DM, Brown EN, Calvo SE, Kohane IS, Kunkel LM

Abstract
Adenosine-to-inosine (A-to-I) RNA editing is a neurodevelopmentally regulated epigenetic modification shown to modulate complex behavior in animals. Little is known about human A-to-I editing, but it is thought to constitute one of many molecular mechanisms connecting environmental stimuli and behavioral outputs. Thus, comprehensive exploration of A-to-I RNA editing in human brains may shed light on gene-environment interactions underlying complex behavior in health and disease. Synaptic function is a main target of A-to-I editing, which can selectively recode key amino acids in synaptic genes, directly altering synaptic strength and duration in response to environmental signals. Here, we performed a high-resolution survey of synaptic A-to-I RNA editing in a human population, and examined how it varies in autism, a neurodevelopmental disorder in which synaptic abnormalities are a common finding. Using ultra-deep (>1000 × ) sequencing, we quantified the levels of A-to-I editing of 10 synaptic genes in postmortem cerebella from 14 neurotypical and 11 autistic individuals. A high dynamic range of editing levels was detected across individuals and editing sites, from 99.6% to below detection limits. In most sites, the extreme ends of the population editing distributions were individuals with autism. Editing was correlated with isoform usage, clusters of correlated sites were identified, and differential editing patterns examined. Finally, a dysfunctional form of the editing enzyme adenosine deaminase acting on RNA B1 was found more commonly in postmortem cerebella from individuals with autism. These results provide a population-level, high-resolution view of A-to-I RNA editing in human cerebella and suggest that A-to-I editing of synaptic genes may be informative for assessing the epigenetic risk for autism.

PMID: 22869036 [PubMed - indexed for MEDLINE]

Allelic expression analysis in the brain suggests a role for heterogeneous insults affecting epigenetic processes in autism spectrum disorders.

March 25, 2014 - 6:02am

Allelic expression analysis in the brain suggests a role for heterogeneous insults affecting epigenetic processes in autism spectrum disorders.

Hum Mol Genet. 2014 Mar 21;

Authors: Ben-David E, Shohat S, Shifman S

Abstract
Monoallelic expression, including genomic imprinting, X-chromosome inactivation and random monoallelic expression of autosomal genes are epigenetic phenomena. Genes that are expressed in a monoallelic way may be more vulnerable to genetic or epigenetic mutations. Thus, comprehensive exploration of monoallelic expression in human brains may shed light on complex brain disorders. Autism-related disorders are known to be associated with imprinted genes on chromosome 15. However, it is not clear if other imprinted regions or other types of monoallelic expression are associated with autism spectrum disorder (ASD). Here, we performed a genome-wide survey of allele expression imbalance (AEI) in the human brain using single nucleotide polymorphisms (SNPs), in 18 individuals with ASD and 15 controls. Individuals with ASD had the most extreme number of monoallelic expressed SNPs in both the autosomes and the X chromosome. In two cases that were studied in detail the monoallelic expression was confined to specific brain region or cell type. Using these data we were also able to define the allelic expression status of known imprinted genes in the human brain, and to identify abnormal imprinting in an individual with ASD. Lastly, we developed an analysis of individual level expression, focusing on the difference of each individual from the mean. We found that individuals with ASD had more genes that were up or down-regulated in an individual-specific manner. We also identified pathways perturbed in specific individuals. These results underline the heterogeneity in gene regulation in ASD, at the level of both allelic and total expression.

PMID: 24659497 [PubMed - as supplied by publisher]

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

March 25, 2014 - 6:02am

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

Peptides. 2014 Mar 20;

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 - as supplied by publisher]

Neurodevelopmental outcome in Angelman syndrome: Genotype-phenotype correlations.

March 25, 2014 - 6:02am

Neurodevelopmental outcome in Angelman syndrome: Genotype-phenotype correlations.

Res Dev Disabil. 2014 Mar 18;

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 - as supplied by publisher]

Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality.

March 25, 2014 - 6:02am
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Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality.

Nat Neurosci. 2014 Feb;17(2):240-7

Authors: Huang TN, Chuang HC, Chou WH, Chen CY, Wang HF, Chou SJ, Hsueh YP

Abstract
The neuron-specific transcription factor T-box brain 1 (TBR1) regulates brain development. Disruptive mutations in the TBR1 gene have been repeatedly identified in patients with autism spectrum disorders (ASDs). Here, we show that Tbr1 haploinsufficiency results in defective axonal projections of amygdalar neurons and the impairment of social interaction, ultrasonic vocalization, associative memory and cognitive flexibility in mice. Loss of a copy of the Tbr1 gene altered the expression of Ntng1, Cntn2 and Cdh8 and reduced both inter- and intra-amygdalar connections. These developmental defects likely impair neuronal activation upon behavioral stimulation, which is indicated by fewer c-FOS-positive neurons and lack of GRIN2B induction in Tbr1(+/-) amygdalae. We also show that upregulation of amygdalar neuronal activity by local infusion of a partial NMDA receptor agonist, d-cycloserine, ameliorates the behavioral defects of Tbr1(+/-) mice. Our study suggests that TBR1 is important in the regulation of amygdalar axonal connections and cognition.

PMID: 24441682 [PubMed - indexed for MEDLINE]

Association of rs2129575 in the tryptophan hydroxylase 2 gene with clinical phenotypes of autism spectrum disorders.

March 25, 2014 - 6:02am
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Association of rs2129575 in the tryptophan hydroxylase 2 gene with clinical phenotypes of autism spectrum disorders.

Psychiatry Clin Neurosci. 2013 Sep;67(6):457-8

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

PMID: 23992289 [PubMed - indexed for MEDLINE]

Sociocommunicative and sensorimotor impairments in male P2X4-deficient mice.

March 25, 2014 - 6:02am
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Sociocommunicative and sensorimotor impairments in male P2X4-deficient mice.

Neuropsychopharmacology. 2013 Sep;38(10):1993-2002

Authors: Wyatt LR, Godar SC, Khoja S, Jakowec MW, Alkana RL, Bortolato M, Davies DL

Abstract
Purinergic P2X receptors are a family of ligand-gated ion channels gated by extracellular adenosine 5'-triphosphate (ATP). Of the seven P2X subtypes, P2X4 receptors (P2X4Rs) are richly expressed in the brain, yet their role in behavioral organization remains poorly understood. In this study, we examined the behavioral responses of P2X4R heterozygous (HZ) and knockout (KO) mice in a variety of testing paradigms designed to assess complementary aspects of sensory functions, emotional reactivity, and cognitive organization. P2X4R deficiency did not induce significant alterations of locomotor activity and anxiety-related indices in the novel open field and elevated plus-maze tests. Conversely, P2X4R KO mice displayed marked deficits in acoustic startle reflex amplitude, as well as significant sensorimotor gating impairments, as assessed by the prepulse inhibition of the startle. In addition, P2X4R KO mice displayed enhanced tactile sensitivity, as signified by a lower latency in the sticky-tape removal test. Moreover, both P2X4R HZ and KO mice showed significant reductions in social interaction and maternal separation-induced ultrasonic vocalizations in pups. Notably, brain regions of P2X4R KO mice exhibited significant brain-regional alterations in the subunit composition of glutamate ionotropic receptors. These results collectively document that P2X4-deficient mice exhibit a spectrum of phenotypic abnormalities partially akin to those observed in other murine models of autism-spectrum disorder. In conclusion, our findings highlight a putative role of P2X4Rs in the regulation of perceptual and sociocommunicative functions and point to these receptors as putative targets for disturbances associated with neurodevelopmental disorders.

PMID: 23604007 [PubMed - indexed for MEDLINE]

An eQTL mapping approach reveals that rare variants in the SEMA5A regulatory network impact autism risk.

March 25, 2014 - 6:02am
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An eQTL mapping approach reveals that rare variants in the SEMA5A regulatory network impact autism risk.

Hum Mol Genet. 2013 Jul 15;22(14):2960-72

Authors: Cheng Y, Quinn JF, Weiss LA

Abstract
To date, genome-wide single nucleotide polymorphism (SNP) and copy number variant (CNV) association studies of autism spectrum disorders (ASDs) have led to promising signals but not to easily interpretable or translatable results. Our own genome-wide association study (GWAS) showed significant association to an intergenic SNP near Semaphorin 5A (SEMA5A) and provided evidence for reduced expression of the same gene. In a novel GWAS follow-up approach, we map an expression regulatory pathway for a GWAS candidate gene, SEMA5A, in silico by using population expression and genotype data sets. We find that the SEMA5A regulatory network significantly overlaps rare autism-specific CNVs. The SEMA5A regulatory network includes previous autism candidate genes and regions, including MACROD2, A2BP1, MCPH1, MAST4, CDH8, CADM1, FOXP1, AUTS2, MBD5, 7q21, 20p, USH2A, KIRREL3, DBF4B and RELN, among others. Our results provide: (i) a novel data-derived network implicated in autism, (ii) evidence that the same pathway seeded by an initial SNP association shows association with rare genetic variation in ASDs, (iii) a potential mechanism of action and interpretation for the previous autism candidate genes and genetic variants that fall in this network, and (iv) a novel approach that can be applied to other candidate genes for complex genetic disorders. We take a step towards better understanding of the significance of SEMA5A pathways in autism that can guide interpretation of many other genetic results in ASDs.

PMID: 23575222 [PubMed - indexed for MEDLINE]

DUF1220 Dosage Is Linearly Associated with Increasing Severity of the Three Primary Symptoms of Autism.

March 22, 2014 - 8:20am
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DUF1220 Dosage Is Linearly Associated with Increasing Severity of the Three Primary Symptoms of Autism.

PLoS Genet. 2014 Mar;10(3):e1004241

Authors: Davis JM, Searles VB, Anderson N, Keeney J, Dumas L, Sikela JM

Abstract
One of the three most frequently documented copy number variations associated with autism spectrum disorder (ASD) is a 1q21.1 duplication that encompasses sequences encoding DUF1220 protein domains, the dosage of which we previously implicated in increased human brain size. Further, individuals with ASD frequently display accelerated brain growth and a larger brain size that is also associated with increased symptom severity. Given these findings, we investigated the relationship between DUF1220 copy number and ASD severity, and here show that in individuals with ASD (n = 170), the copy number (dosage) of DUF1220 subtype CON1 is highly variable, ranging from 56 to 88 copies following a Gaussian distribution. More remarkably, in individuals with ASD CON1 copy number is also linearly associated, in a dose-response manner, with increased severity of each of the three primary symptoms of ASD: social deficits (p = 0.021), communicative impairments (p = 0.030), and repetitive behaviors (p = 0.047). These data indicate that DUF1220 protein domain (CON1) dosage has an ASD-wide effect and, as such, is likely to be a key component of a major pathway underlying ASD severity. Finally, these findings, by implicating the dosage of a previously unexamined, copy number polymorphic and brain evolution-related gene coding sequence in ASD severity, provide an important new direction for further research into the genetic factors underlying ASD.

PMID: 24651471 [PubMed - in process]

Integrating multiple genomic data to predict disease-causing nonsynonymous single nucleotide variants in exome sequencing studies.

March 22, 2014 - 8:20am
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Integrating multiple genomic data to predict disease-causing nonsynonymous single nucleotide variants in exome sequencing studies.

PLoS Genet. 2014 Mar;10(3):e1004237

Authors: Wu J, Li Y, Jiang R

Abstract
Exome sequencing has been widely used in detecting pathogenic nonsynonymous single nucleotide variants (SNVs) for human inherited diseases. However, traditional statistical genetics methods are ineffective in analyzing exome sequencing data, due to such facts as the large number of sequenced variants, the presence of non-negligible fraction of pathogenic rare variants or de novo mutations, and the limited size of affected and normal populations. Indeed, prevalent applications of exome sequencing have been appealing for an effective computational method for identifying causative nonsynonymous SNVs from a large number of sequenced variants. Here, we propose a bioinformatics approach called SPRING (Snv PRioritization via the INtegration of Genomic data) for identifying pathogenic nonsynonymous SNVs for a given query disease. Based on six functional effect scores calculated by existing methods (SIFT, PolyPhen2, LRT, MutationTaster, GERP and PhyloP) and five association scores derived from a variety of genomic data sources (gene ontology, protein-protein interactions, protein sequences, protein domain annotations and gene pathway annotations), SPRING calculates the statistical significance that an SNV is causative for a query disease and hence provides a means of prioritizing candidate SNVs. With a series of comprehensive validation experiments, we demonstrate that SPRING is valid for diseases whose genetic bases are either partly known or completely unknown and effective for diseases with a variety of inheritance styles. In applications of our method to real exome sequencing data sets, we show the capability of SPRING in detecting causative de novo mutations for autism, epileptic encephalopathies and intellectual disability. We further provide an online service, the standalone software and genome-wide predictions of causative SNVs for 5,080 diseases at http://bioinfo.au.tsinghua.edu.cn/spring.

PMID: 24651380 [PubMed - in process]

Branched-Chain Amino Acid Metabolism: From Rare Mendelian Diseases to More Common Disorders.

March 22, 2014 - 8:20am
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Branched-Chain Amino Acid Metabolism: From Rare Mendelian Diseases to More Common Disorders.

Hum Mol Genet. 2014 Mar 20;

Authors: Burrage LC, Nagamani SC, Campeau PM, Lee BH

Abstract
Branched-chain amino acid (BCAA) metabolism plays a central role in the pathophysiology of both rare inborn errors of metabolism and the more common multi-factorial diseases. Although deficiency of the branched-chain ketoacid dehydrogenase (BCKDC) and associated elevations in the BCAAs and their ketoacids have been recognized as the cause of maple syrup urine disease (MSUD) for decades, treatment options for this disorder have been limited to dietary interventions. In recent years, the discovery of improved leucine tolerance after liver transplantation has resulted in a new therapeutic strategy for this disorder. Likewise, targeting the regulation of the BCKDC activity may be an alternative potential treatment strategy for MSUD. The regulation of the BCKDC by the branched-chain ketoacid dehydrogenase kinase (BCKDK) has also been implicated in a new inborn error of metabolism characterized by autism, intellectual disability, and seizures. Lastly, there is a growing body of literature implicating BCAA metabolism in more common disorders such as the metabolic syndrome, cancer, and hepatic disease. This review surveys the knowledge acquired on the topic over the past 50 years and focuses on recent developments in the field of BCAA metabolism.

PMID: 24651065 [PubMed - as supplied by publisher]

Genetic Evidence for the Adhesion Protein IgSF9/Dasm1 to Regulate Inhibitory Synapse Development Independent of its Intracellular Domain.

March 22, 2014 - 8:20am
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Genetic Evidence for the Adhesion Protein IgSF9/Dasm1 to Regulate Inhibitory Synapse Development Independent of its Intracellular Domain.

J Neurosci. 2014 Mar 19;34(12):4187-99

Authors: Mishra A, Traut MH, Becker L, Klopstock T, Stein V, Klein R

Abstract
Normal brain function requires balanced development of excitatory and inhibitory synapses. An imbalance in synaptic transmission underlies many brain disorders such as epilepsy, schizophrenia, and autism. Compared with excitatory synapses, relatively little is known about the molecular control of inhibitory synapse development. We used a genetic approach in mice to identify the Ig superfamily member IgSF9/Dasm1 as a candidate homophilic synaptic adhesion protein that regulates inhibitory synapse development. IgSF9 is expressed in pyramidal cells and subsets of interneurons in the CA1 region of hippocampus. Electrophysiological recordings of acute hippocampal slices revealed that genetic inactivation of the IgSF9 gene resulted in fewer functional inhibitory synapses; however, the strength of the remaining synapses was unaltered. These physiological abnormalities were correlated with decreased expression of inhibitory synapse markers in IgSF9(-/-) mice, providing anatomical evidence for a reduction in inhibitory synapse numbers, whereas excitatory synapse development was normal. Surprisingly, knock-in mice expressing a mutant isoform of IgSF9 lacking the entire cytoplasmic domain (IgSF9(ΔC/ΔC) mice) had no defects in inhibitory synapse development, providing genetic evidence that IgSF9 regulates synapse development via ectodomain interactions rather than acting itself as a signaling receptor. Further, we found that IgSF9 mediated homotypic binding and cell aggregation, but failed to induce synapse formation, suggesting that IgSF9 acts as a cell adhesion molecule (CAM) to maintain synapses. Juvenile IgSF9(-/-) mice exhibited increased seizure susceptibility indicative of an imbalance in synaptic excitation and inhibition. These results provide genetic evidence for a specific role of IgSF9 in inhibitory synapse development/maintenance, presumably by its CAM-like activity.

PMID: 24647940 [PubMed - in process]

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