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A Diffusion Tensor Imaging Study in Children With ADHD, Autism Spectrum Disorder, OCD, and Matched Controls: Distinct and Non-Distinct White Matter Disruption and Dimensional Brain-Behavior Relationships.

July 2, 2016 - 7:04am

A Diffusion Tensor Imaging Study in Children With ADHD, Autism Spectrum Disorder, OCD, and Matched Controls: Distinct and Non-Distinct White Matter Disruption and Dimensional Brain-Behavior Relationships.

Am J Psychiatry. 2016 Jul 1;:appiajp201615111435

Authors: Ameis SH, Lerch JP, Taylor MJ, Lee W, Viviano JD, Pipitone J, Nazeri A, Croarkin PE, Voineskos AN, Lai MC, Crosbie J, Brian J, Soreni N, Schachar R, Szatmari P, Arnold PD, Anagnostou E

Abstract
OBJECTIVE: Neurodevelopmental disorders (NDDs) (attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) share genetic vulnerability and symptom domains. The authors present direct comparison of structural brain circuitry in children and adolescents with NDDs and control subjects and examine brain circuit-behavior relationships across NDDs using dimensional measures related to each disorder.
METHOD: Diffusion imaging and behavioral measures were acquired in 200 children and adolescents (ADHD: N=31; OCD: N=36; ASD: N=71; controls: N=62; mean age range: 10.3-12.6 years). Following Tract-Based Spatial Statistics, multigroup comparison of white matter indices was conducted, followed by pairwise comparisons. Relationships of fractional anisotropy with dimensional measures of inattention, social deficits, obsessive-compulsive symptoms, and general adaptive functioning were conducted across the NDD sample.
RESULTS: Lower fractional anisotropy within the splenium of the corpus callosum was found in each NDD group, compared with the control group. Lower fractional anisotropy in additional white matter tracts was found in the ASD and ADHD groups, compared with the control group, but not in the OCD group. Fractional anisotropy was lower in the ASD and ADHD groups compared with the OCD group but was not different in ADHD participants compared with ASD participants. A positive relation between fractional anisotropy (across much of the brain) and general adaptive functioning across NDDs was shown.
CONCLUSIONS: This study identified disruption in interhemispheric circuitry (i.e., fractional anisotropy alterations in the corpus callosum) as a shared feature of ASD, ADHD, and OCD. However, fractional anisotropy alterations may be more widespread and severe in ASD and ADHD than in OCD. Higher fractional anisotropy throughout the brain appears to be related to better adaptive function across NDDs.

PMID: 27363509 [PubMed - as supplied by publisher]

Ranbp1, Deleted in DiGeorge/22q11.2 Deletion Syndrome, is a Microcephaly Gene That Selectively Disrupts Layer 2/3 Cortical Projection Neuron Generation.

July 2, 2016 - 7:04am
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Ranbp1, Deleted in DiGeorge/22q11.2 Deletion Syndrome, is a Microcephaly Gene That Selectively Disrupts Layer 2/3 Cortical Projection Neuron Generation.

Cereb Cortex. 2015 Oct;25(10):3977-93

Authors: Paronett EM, Meechan DW, Karpinski BA, LaMantia AS, Maynard TM

Abstract
Ranbp1, a Ran GTPase-binding protein implicated in nuclear/cytoplasmic trafficking, is included within the DiGeorge/22q11.2 Deletion Syndrome (22q11.2 DS) critical region associated with behavioral impairments including autism and schizophrenia. Ranbp1 is highly expressed in the developing forebrain ventricular/subventricular zone but has no known obligate function during brain development. We assessed the role of Ranbp1 in a targeted mouse mutant. Ranbp1(-/-) mice are not recovered live at birth, and over 60% of Ranbp1(-/-) embryos are exencephalic. Non-exencephalic Ranbp1(-/-) embryos are microcephalic, and proliferation of cortical progenitors is altered. At E10.5, radial progenitors divide more slowly in the Ranpb1(-/-) dorsal pallium. At E14.5, basal, but not apical/radial glial progenitors, are compromised in the cortex. In both E10.5 apical and E14.5 basal progenitors, M phase of the cell cycle appears selectively retarded by loss of Ranpb1 function. Ranbp1(-/-)-dependent proliferative deficits substantially diminish the frequency of layer 2/3, but not layer 5/6 cortical projection neurons. Ranbp1(-/-) cortical phenotypes parallel less severe alterations in LgDel mice that carry a deletion parallel to many (but not all) 22q11.2 DS patients. Thus, Ranbp1 emerges as a microcephaly gene within the 22q11.2 deleted region that may contribute to altered cortical precursor proliferation and neurogenesis associated with broader 22q11.2 deletion.

PMID: 25452572 [PubMed - indexed for MEDLINE]

DNA methylation signature of human fetal alcohol spectrum disorder.

July 1, 2016 - 7:01am

DNA methylation signature of human fetal alcohol spectrum disorder.

Epigenetics Chromatin. 2016;9:25

Authors: Portales-Casamar E, Lussier AA, Jones MJ, MacIsaac JL, Edgar RD, Mah SM, Barhdadi A, Provost S, Lemieux-Perreault LP, Cynader MS, Chudley AE, Dubé MP, Reynolds JN, Pavlidis P, Kobor MS

Abstract
BACKGROUND: Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of alcohol's effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with fetal alcohol spectrum disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date.
METHODS: Genome-wide DNA methylation patterns of buccal epithelial cells (BECs) were analyzed using the Illumina HumanMethylation450 array in a Canadian cohort of 206 children (110 FASD and 96 controls). Genotyping was performed in parallel using the Infinium HumanOmni2.5-Quad v1.0 BeadChip.
RESULTS: After correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns. Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders.
CONCLUSIONS: These findings suggested that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD.

PMID: 27358653 [PubMed]

Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells.

July 1, 2016 - 7:01am
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Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells.

Immunity. 2016 Feb 16;44(2):380-90

Authors: Kawalekar OU, O'Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD, Patel PR, Guedan S, Scholler J, Keith B, Snyder N, Blair I, Milone MC, June CH

Abstract
Chimeric antigen receptors (CARs) redirect T cell cytotoxicity against cancer cells, providing a promising approach to cancer immunotherapy. Despite extensive clinical use, the attributes of CAR co-stimulatory domains that impact persistence and resistance to exhaustion of CAR-T cells remain largely undefined. Here, we report the influence of signaling domains of coreceptors CD28 and 4-1BB on the metabolic characteristics of human CAR T cells. Inclusion of 4-1BB in the CAR architecture promoted the outgrowth of CD8(+) central memory T cells that had significantly enhanced respiratory capacity, increased fatty acid oxidation and enhanced mitochondrial biogenesis. In contrast, CAR T cells with CD28 domains yielded effector memory cells with a genetic signature consistent with enhanced glycolysis. These results provide, at least in part, a mechanistic insight into the differential persistence of CAR-T cells expressing 4-1BB or CD28 signaling domains in clinical trials and inform the design of future CAR T cell therapies.

PMID: 26885860 [PubMed - indexed for MEDLINE]

Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice.

June 30, 2016 - 10:00am
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Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice.

J Neurosci. 2016 Feb 17;36(7):2131-47

Authors: Guo W, Molinaro G, Collins KA, Hays SA, Paylor R, Worley PF, Szumlinski KK, Huber KM

Abstract
UNLABELLED: Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmr1 knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmr1 KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, H1a, rescues many phenotypes of Fmr1 KO mice. These results suggested that disruption of mGlu5-Homer leads to phenotypes of FXS. To test this idea, we examined mice with a knockin mutation of mGlu5 (F1128R; mGlu5(R/R)) that abrogates binding to Homer. Although FMRP levels were normal, mGlu5(R/R) mice mimicked multiple phenotypes of Fmr1 KO mice, including reduced mGlu5 association with the postsynaptic density, enhanced constitutive mGlu5 signaling to protein synthesis, deficits in agonist-induced translational control, protein synthesis-independent LTD, neocortical hyperexcitability, audiogenic seizures, and altered behaviors, including anxiety and sensorimotor gating. These results reveal new roles for the Homer scaffolds in regulation of mGlu5 function and implicate a specific molecular mechanism in a complex brain disease.
SIGNIFICANCE STATEMENT: Abnormal function of the metabotropic, or Gq-coupled, glutamate receptor 5 (mGlu5) has been implicated in neurodevelopmental disorders, including a genetic cause of intellectual disability and autism called fragile X syndrome. In brains of a mouse model of fragile X, mGlu5 is less associated with its binding partner Homer, a scaffolding protein that regulates mGlu5 localization to synapses and its ability to activate biochemical signaling pathways. Here we show that a mouse expressing a mutant mGlu5 that cannot bind to Homer is sufficient to mimic many of the biochemical, neurophysiological, and behavioral symptoms observed in the fragile X mouse. This work provides strong evidence that Homer-mGlu5 binding contributes to symptoms associated with neurodevelopmental disorders.

PMID: 26888925 [PubMed - indexed for MEDLINE]

Genetic Evidence for Possible Involvement of the Calcium Channel Gene CACNA1A in Autism Pathogenesis in Chinese Han Population.

June 30, 2016 - 10:00am
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Genetic Evidence for Possible Involvement of the Calcium Channel Gene CACNA1A in Autism Pathogenesis in Chinese Han Population.

PLoS One. 2015;10(11):e0142887

Authors: Li J, You Y, Yue W, Jia M, Yu H, Lu T, Wu Z, Ruan Y, Wang L, Zhang D

Abstract
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders. Recent studies suggested that calcium channel genes might be involved in the genetic etiology of ASD. CACNA1A, encoding an alpha-1 subunit of voltage-gated calcium channel, has been reported to play an important role in neural development. Previous study detected that a single nucleotide polymorphism (SNP) in CACNA1A confers risk to ASD in Central European population. However, the genetic relationship between autism and CACNA1A in Chinese Han population remains unclear. To explore the association of CACNA1A with autism, we performed a family-based association study. First, we carried out a family-based association test between twelve tagged SNPs and autism in 239 trios. To further confirm the association, the sample size was expanded to 553 trios by recruiting 314 additional trios. In a total of 553 trios, we identified association of rs7249246 and rs12609735 with autism though this would not survive after Bonferroni correction. Our findings suggest that CACNA1A might play a role in the etiology of autism.

PMID: 26566276 [PubMed - indexed for MEDLINE]

An epigenetic view of developmental diseases: new targets, new therapies.

June 29, 2016 - 6:59pm
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An epigenetic view of developmental diseases: new targets, new therapies.

World J Pediatr. 2016 Aug;12(3):291-297

Authors: Xie P, Zang LQ, Li XK, Shu Q

Abstract
BACKGROUND: Function of epigenetic modifications is one of the most competitive fields in life science. Over the past several decades, it has been revealed that epigenetic modifications play essential roles in development and diseases including developmental diseases. In the present review, we summarize the recent progress about the function of epigenetic regulation, especially DNA and RNA modifications in developmental diseases.
DATA SOURCES: Original research articles and literature reviews published in PubMed-indexed journals.
RESULTS: DNA modifications including methylation and demethylation can regulate gene expression, and are involved in development and multiple diseases including Rett syndrome, Autism spectrum disorders, congenital heart disease and cancer, etc. RNA methylation and demethylation play important roles in RNA processing, reprogramming, circadian, and neuronal activity, and then modulate development.
CONCLUSIONS: DNA and RNA modifications play important roles in development and diseases through regulating gene expression. Epigenetic components could serve as novel targets for the treatment of developmental diseases.

PMID: 27351564 [PubMed - as supplied by publisher]

Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.

June 29, 2016 - 6:59pm
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Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.

Neuron. 2016 Feb 17;89(4):725-33

Authors: Hoffman EJ, Turner KJ, Fernandez JM, Cifuentes D, Ghosh M, Ijaz S, Jain RA, Kubo F, Bill BR, Baier H, Granato M, Barresi MJ, Wilson SW, Rihel J, State MW, Giraldez AJ

Abstract
Autism spectrum disorders (ASDs) are a group of devastating neurodevelopmental syndromes that affect up to 1 in 68 children. Despite advances in the identification of ASD risk genes, the mechanisms underlying ASDs remain unknown. Homozygous loss-of-function mutations in Contactin Associated Protein-like 2 (CNTNAP2) are strongly linked to ASDs. Here we investigate the function of Cntnap2 and undertake pharmacological screens to identify phenotypic suppressors. We find that zebrafish cntnap2 mutants display GABAergic deficits, particularly in the forebrain, and sensitivity to drug-induced seizures. High-throughput behavioral profiling identifies nighttime hyperactivity in cntnap2 mutants, while pharmacological testing reveals dysregulation of GABAergic and glutamatergic systems. Finally, we find that estrogen receptor agonists elicit a behavioral fingerprint anti-correlative to that of cntnap2 mutants and show that the phytoestrogen biochanin A specifically reverses the mutant behavioral phenotype. These results identify estrogenic compounds as phenotypic suppressors and illuminate novel pharmacological pathways with relevance to autism.

PMID: 26833134 [PubMed - indexed for MEDLINE]

CNVs in neuropsychiatric disorders.

June 29, 2016 - 6:59pm
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CNVs in neuropsychiatric disorders.

Hum Mol Genet. 2015 Oct 15;24(R1):R45-9

Authors: Kirov G

Abstract
Over the last few years at least 11 copy number variations (CNVs) have been shown convincingly to increase risk to developing schizophrenia: deletions at 1q21.1, NRXN1, 3q29, 15q11.2, 15q13.3 and 22q11.2, and duplications at 1q21.1, 7q11.23, 15q11.2-q13.1, 16p13.1 and proximal 16p11.2. They are very rare, found cumulatively in 2.4% of patients with schizophrenia and in only 0.5% of controls. They all increase risk for other neurodevelopmental disorders, such as developmental delay and autism spectrum disorders, where they are found at higher rates (3.3%). Their involvement in bipolar affective disorder is much less prominent. All of them affect multiple genes (apart from NRXN1) and cause substantial increases in risk to develop schizophrenia (odds ratios of 2 to over 50). Their penetrance for any neurodevelopmental disorder is high, from ∼10% to nearly 100%. Carriers of these CNVs display cognitive deficits, even when free of neuropsychiatric disorders.

PMID: 26130694 [PubMed - indexed for MEDLINE]

Zfrp8 forms a complex with fragile-X mental retardation protein and regulates its localization and function.

June 28, 2016 - 9:56am
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Zfrp8 forms a complex with fragile-X mental retardation protein and regulates its localization and function.

Dev Biol. 2016 Feb 15;410(2):202-12

Authors: Tan W, Schauder C, Naryshkina T, Minakhina S, Steward R

Abstract
Fragile-X syndrome is the most commonly inherited cause of autism and mental disabilities. The Fmr1 (Fragile-X Mental Retardation 1) gene is essential in humans and Drosophila for the maintenance of neural stem cells, and Fmr1 loss results in neurological and reproductive developmental defects in humans and flies. FMRP (Fragile-X Mental Retardation Protein) is a nucleo-cytoplasmic shuttling protein, involved in mRNA silencing and translational repression. Both Zfrp8 and Fmr1 have essential functions in the Drosophila ovary. In this study, we identified FMRP, Nufip (Nuclear Fragile-X Mental Retardation Protein-interacting Protein) and Tral (Trailer Hitch) as components of a Zfrp8 protein complex. We show that Zfrp8 is required in the nucleus, and controls localization of FMRP in the cytoplasm. In addition, we demonstrate that Zfrp8 genetically interacts with Fmr1 and tral in an antagonistic manner. Zfrp8 and FMRP both control heterochromatin packaging, also in opposite ways. We propose that Zfrp8 functions as a chaperone, controlling protein complexes involved in RNA processing in the nucleus.

PMID: 26772998 [PubMed - indexed for MEDLINE]

Heterozygous Disruption of Autism susceptibility candidate 2 Causes Impaired Emotional Control and Cognitive Memory.

June 28, 2016 - 9:56am
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Heterozygous Disruption of Autism susceptibility candidate 2 Causes Impaired Emotional Control and Cognitive Memory.

PLoS One. 2015;10(12):e0145979

Authors: Hori K, Nagai T, Shan W, Sakamoto A, Abe M, Yamazaki M, Sakimura K, Yamada K, Hoshino M

Abstract
Mutations in the Autism susceptibility candidate 2 gene (AUTS2) have been associated with a broad range of psychiatric illnesses including autism spectrum disorders, intellectual disability and schizophrenia. We previously demonstrated that the cytoplasmic AUTS2 acts as an upstream factor for the Rho family small GTPase Rac1 and Cdc42 that regulate the cytoskeletal rearrangements in neural cells. Moreover, genetic ablation of the Auts2 gene in mice has resulted in defects in neuronal migration and neuritogenesis in the developing cerebral cortex caused by inactivation of Rac1-signaling pathway, suggesting that AUTS2 is required for neural development. In this study, we conducted a battery of behavioral analyses on Auts2 heterozygous mutant mice to examine the involvement of Auts2 in adult cognitive brain functions. Auts2-deficient mice displayed a decrease in exploratory behavior as well as lower anxiety-like behaviors in the absence of any motor dysfunction. Furthermore, the capability for novel object recognition and cued associative memory were impaired in Auts2 mutant mice. Social behavior and sensory motor gating functions were, however, normal in the mutant mice as assessed by the three-chamber test and prepulse inhibition test, respectively. Together, our findings indicate that AUTS2 is critical for the acquisition of neurocognitive function.

PMID: 26717414 [PubMed - indexed for MEDLINE]

Resequencing and Association Analysis of CLN8 with Autism Spectrum Disorder in a Japanese Population.

June 28, 2016 - 9:56am
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Resequencing and Association Analysis of CLN8 with Autism Spectrum Disorder in a Japanese Population.

PLoS One. 2015;10(12):e0144624

Authors: Inoue E, Watanabe Y, Xing J, Kushima I, Egawa J, Okuda S, Hoya S, Okada T, Uno Y, Ishizuka K, Sugimoto A, Igeta H, Nunokawa A, Sugiyama T, Ozaki N, Someya T

Abstract
Rare variations contribute substantially to autism spectrum disorder (ASD) liability. We recently performed whole-exome sequencing in two families with affected siblings and then carried out a follow-up study and identified ceroid-lipofuscinosis neuronal 8 (epilepsy, progressive with mental retardation) (CLN8) as a potential genetic risk factor for ASD. To further investigate the role of CLN8 in the genetic etiology of ASD, we performed resequencing and association analysis of CLN8 with ASD in a Japanese population. Resequencing the CLN8 coding region in 256 ASD patients identified five rare missense variations: g.1719291G>A (R24H), rs201670636 (F39L), rs116605307 (R97H), rs143701028 (T108M) and rs138581191 (N152S). These variations were genotyped in 568 patients (including the resequenced 256 patients) and 1017 controls. However, no significant association between these variations and ASD was identified. This study does not support a contribution of rare missense CLN8 variations to ASD susceptibility in the Japanese population.

PMID: 26657971 [PubMed - indexed for MEDLINE]

Identification of neuromotor deficits common to autism spectrum disorder and attention deficit/hyperactivity disorder, and imitation deficits specific to autism spectrum disorder.

June 28, 2016 - 9:56am
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Identification of neuromotor deficits common to autism spectrum disorder and attention deficit/hyperactivity disorder, and imitation deficits specific to autism spectrum disorder.

Eur Child Adolesc Psychiatry. 2015 Dec;24(12):1497-507

Authors: Biscaldi M, Rauh R, Müller C, Irion L, Saville CW, Schulz E, Klein C

Abstract
Deficits in motor and imitation abilities are a core finding in autism spectrum disorders (ASD), but impaired motor functions are also found in attention deficit/hyperactivity disorder (ADHD). Given recent theorising about potential aetiological overlap between the two disorders, the present study aimed to assess difficulties in motor performance and imitation of facial movements and meaningless gestures in a sample of 24 ADHD patients, 22 patients with ASD, and 20 typically developing children, matched for age (6-13 years) and similar in IQ (>80). Furthermore, we explored the impact of comorbid ADHD symptoms on motor and imitation performance in the ASD sample and the interrelationships between the two groups of variables in the clinical groups separately. The results show motor dysfunction was common to both disorders, but imitation deficits were specific to ASD. Together with the pattern of interrelated motor and imitation abilities, which we found exclusively in the ASD group, our findings suggest complex phenotypic, and possibly aetiological, relationships between the two neurodevelopmental conditions.

PMID: 26233230 [PubMed - indexed for MEDLINE]

The Compassionate Side of Neuroscience: Tony Sermone's Undiagnosed Genetic Journey--ADNP Mutation.

June 28, 2016 - 9:56am
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The Compassionate Side of Neuroscience: Tony Sermone's Undiagnosed Genetic Journey--ADNP Mutation.

J Mol Neurosci. 2015 Aug;56(4):751-7

Authors: Gozes I, Helsmoortel C, Vandeweyer G, Van der Aa N, Kooy F, Sermone SB

PMID: 26168855 [PubMed - indexed for MEDLINE]

Recording Mouse Ultrasonic Vocalizations to Evaluate Social Communication.

June 25, 2016 - 6:50am

Recording Mouse Ultrasonic Vocalizations to Evaluate Social Communication.

J Vis Exp. 2016;(112)

Authors: Ferhat AT, Torquet N, Le Sourd AM, de Chaumont F, Olivo-Marin JC, Faure P, Bourgeron T, Ey E

Abstract
Mice emit ultrasonic vocalizations in different contexts throughout development and in adulthood. These vocal signals are now currently used as proxies for modeling the genetic bases of vocal communication deficits. Characterizing the vocal behavior of mouse models carrying mutations in genes associated with neuropsychiatric disorders such as autism spectrum disorders will help to understand the mechanisms leading to social communication deficits. We provide here protocols to reliably elicit ultrasonic vocalizations in pups and in adult mice. This standardization will help reduce inter-study variability due to the experimental settings. Pup isolation calls are recorded throughout development from individual pups isolated from dam and littermates. In adulthood, vocalizations are recorded during same-sex interactions (without a sexual component) by exposing socially motivated males or females to an unknown same-sex conspecific. We also provide a protocol to record vocalizations from adult males exposed to an estrus female. In this context, there is a sexual component in the interaction. These protocols are established to elicit a large amount of ultrasonic vocalizations in laboratory mice. However, we point out the important inter-individual variability in the vocal behavior of mice, which should be taken into account by recording a minimal number of individuals (at least 12 in each condition). These recordings of ultrasonic vocalizations are used to evaluate the call rate, the vocal repertoire and the acoustic structure of the calls. Data are combined with the analysis of synchronous video recordings to provide a more complete view on social communication in mice. These protocols are used to characterize the vocal communication deficits in mice lacking ProSAP1/Shank2, a gene associated with autism spectrum disorders. More ultrasonic vocalizations recordings can also be found on the mouseTube database, developed to favor the exchange of such data.

PMID: 27341321 [PubMed - as supplied by publisher]

The first patient with tandem duplication of 6q14q16: Molecular and phenotypic characterization.

June 25, 2016 - 6:50am

The first patient with tandem duplication of 6q14q16: Molecular and phenotypic characterization.

Am J Med Genet A. 2016 Jun 23;

Authors: Sanmann JN, Casas KA, Bevilacqua J, Bishay DL, Clark T, Van Dyke AZ, Leiferman PC, Reddi HV, Starr LJ

Abstract
Duplications of the long arm of chromosome 6 have been previously reported in a limited number of patients; however, most reported duplications encompass regions of chromosome 6 distal to band q21. Duplications restricted to the proximal portion of 6q are rare. We report an 8-year-old male with a 16.4 megabase (Mb) tandem duplication of chromosome 6q14.1q16.1 (chr6:78950191-95395865; hg19) who exhibited dysmorphic facial features, seizures, global developmental delay, intellectual disability, autism spectrum disorder, sensorineural hearing loss, and immune deficiency. This patient refines and potentially expands the current, poorly-characterized phenotype associated with duplication of this proximal 6q region. We recommend a low threshold for a hearing evaluation beyond newborn screening and for pursuing an immune work-up in patients with similar 6q duplications. © 2016 Wiley Periodicals, Inc.

PMID: 27338032 [PubMed - as supplied by publisher]

Developmental Defects of Caenorhabditis elegans Lacking Branched-chain α-Ketoacid Dehydrogenase Are Mainly Caused by Monomethyl Branched-chain Fatty Acid Deficiency.

June 25, 2016 - 6:50am
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Developmental Defects of Caenorhabditis elegans Lacking Branched-chain α-Ketoacid Dehydrogenase Are Mainly Caused by Monomethyl Branched-chain Fatty Acid Deficiency.

J Biol Chem. 2016 Feb 5;291(6):2967-73

Authors: Jia F, Cui M, Than MT, Han M

Abstract
Branched-chain α-ketoacid dehydrogenase (BCKDH) catalyzes the critical step in the branched-chain amino acid (BCAA) catabolic pathway and has been the focus of extensive studies. Mutations in the complex disrupt many fundamental metabolic pathways and cause multiple human diseases including maple syrup urine disease (MSUD), autism, and other related neurological disorders. BCKDH may also be required for the synthesis of monomethyl branched-chain fatty acids (mmBCFAs) from BCAAs. The pathology of MSUD has been attributed mainly to BCAA accumulation, but the role of mmBCFA has not been evaluated. Here we show that disrupting BCKDH in Caenorhabditis elegans causes mmBCFA deficiency, in addition to BCAA accumulation. Worms with deficiency in BCKDH function manifest larval arrest and embryonic lethal phenotypes, and mmBCFA supplementation suppressed both without correcting BCAA levels. The majority of developmental defects caused by BCKDH deficiency may thus be attributed to lacking mmBCFAs in worms. Tissue-specific analysis shows that restoration of BCKDH function in multiple tissues can rescue the defects, but is especially effective in neurons. Taken together, we conclude that mmBCFA deficiency is largely responsible for the developmental defects in the worm and conceivably might also be a critical contributor to the pathology of human MSUD.

PMID: 26683372 [PubMed - indexed for MEDLINE]

Validity and reliability analysis of the Chinese parent version of the Autism Spectrum Rating Scale (6-18 years).

June 25, 2016 - 6:50am
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Validity and reliability analysis of the Chinese parent version of the Autism Spectrum Rating Scale (6-18 years).

Psychiatry Res. 2015 Dec 15;230(2):255-61

Authors: Zhou H, Zhang L, Wu L, Zou X, Luo X, Xia K, Wang Y, Xu X, Ge X, Sun C, Deng H, Fombonne E, Jiang YH, Yan W, Wang Y

Abstract
This study aimed to investigate the validity and reliability of the Chinese parent version of the Autism Spectrum Rating Scale (ASRS, 6-18 years) for a general sample of Chinese children. The study involved assessing 1625 community-based subjects aged 6-12 years from four sites (Shanghai, Guangzhou, Changsha, and Harbin city) in China and 211 clinic-based participants aged 6-18 with a confirmed diagnosis of autism spectrum disorders (ASDs). The internal consistency (Cronbach's alpha) ranged from 0.585 to 0.929, and the test-retest reliability (interclass correlations) ranged from 0.542 to 0.749, indicating no significant difference between the two tests at an interval of 2-4 weeks. The construct validity was relatively excellent, and the concurrent validity with the Social Responsiveness Scale (SRS) (Pearson correlations) was 0.732 between the two total scores. Receiver operating characteristics (ROC) analyses showed excellent and comparable discriminant validity of the ASRS with respect to the SRS, with an area under the curve (AUC) of 0.9507 (95% CI: 0.93-0.97) versus 0.9703 (95% CI: 0.96-0.98), respectively. Our data suggested a cutoff ≥60 for the Chinese version of the ASRS, with good accuracy in screening autism symptoms (sensitivity=94.2%, specificity=77%). The Chinese parent version of the ASRS is therefore a reliable and valid tool for screening autistic symptoms in Chinese children in general.

PMID: 26384573 [PubMed - indexed for MEDLINE]

1q21.1 microduplication in a patient with mental impairment and congenital heart defect.

June 25, 2016 - 6:50am
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1q21.1 microduplication in a patient with mental impairment and congenital heart defect.

Mol Med Rep. 2015 Oct;12(4):5655-8

Authors: Sun G, Tan Z, Fan L, Wang J, Yang Y, Zhang W

Abstract
1q21.1 duplication is a rare copy number variant with multiple congenital malformations, including developmental delay, autism spectrum disorder, dysmorphic features and congenital heart anomalies. The present study described a Chinese female patient (age, four years and eight months) with multiple malformations, including congenital heart defect, mental impairment and developmental delay. The parents and the monozygotic twin sister of the patient, however, were physically and psychologically normal. High‑resolution genome‑wide single nucleotide polymorphism array revealed a 1.6‑Mb duplication in chromosome region 1q21.1. This chromosome region contained HFE2, a critical gene involved in hereditary hemochromatosis. However, the parents and monozygotic twin sister of the patient did not carry this genomic lesion. To the best of our knowledge, the present study was the first to report on a 1q21.1 duplication patient in mainland China.

PMID: 26238956 [PubMed - indexed for MEDLINE]

Phylogenetic Analysis Supports a Link between DUF1220 Domain Number and Primate Brain Expansion.

June 25, 2016 - 6:50am
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Phylogenetic Analysis Supports a Link between DUF1220 Domain Number and Primate Brain Expansion.

Genome Biol Evol. 2015 Aug;7(8):2083-8

Authors: Zimmer F, Montgomery SH

Abstract
The expansion of DUF1220 domain copy number during human evolution is a dramatic example of rapid and repeated domain duplication. Although patterns of expression, homology, and disease associations suggest a role in cortical development, this hypothesis has not been robustly tested using phylogenetic methods. Here, we estimate DUF1220 domain counts across 12 primate genomes using a nucleotide Hidden Markov Model. We then test a series of hypotheses designed to examine the potential evolutionary significance of DUF1220 copy number expansion. Our results suggest a robust association with brain size, and more specifically neocortex volume. In contradiction to previous hypotheses, we find a strong association with postnatal brain development but not with prenatal brain development. Our results provide further evidence of a conserved association between specific loci and brain size across primates, suggesting that human brain evolution may have occurred through a continuation of existing processes.

PMID: 26112965 [PubMed - indexed for MEDLINE]

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