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Abnormalities in the Structure and Function of Cerebellar Neurons and Neuroglia in the Lc/+ Chimeric Mouse Model of Variable Developmental Purkinje Cell Loss.

February 4, 2016 - 7:29am

Abnormalities in the Structure and Function of Cerebellar Neurons and Neuroglia in the Lc/+ Chimeric Mouse Model of Variable Developmental Purkinje Cell Loss.

Cerebellum. 2016 Feb 2;

Authors: Cairns J, Swanson D, Yeung J, Sinova A, Chan R, Potluri P, Dickson P, Mittleman G, Goldowitz D

Abstract
Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by impaired and disordered language, decreased social interactions, stereotyped and repetitive behaviors, and impaired fine and gross motor skills. It has been well established that cerebellar abnormalities are one of the most common structural changes seen in the brains of people diagnosed with autism. Common cerebellar pathology observed in autistic individuals includes variable loss of cerebellar Purkinje cells (PCs) and increased numbers of reactive neuroglia in the cerebellum and cortical brain regions. The Lc/+ mutant mouse loses 100 % of cerebellar PCs during the first few weeks of life and provided a valuable model to study the effects of developmental PC loss on underlying structural and functional changes in cerebellar neural circuits. Lurcher (Lc) chimeric mice were also generated to explore the link between variable cerebellar pathology and subsequent changes in the structure and function of cerebellar neurons and neuroglia. Chimeras with the most severe cerebellar pathology (as quantified by cerebellar PC counts) had the largest changes in cFos expression (an indirect reporter of neural activity) in cerebellar granule cells (GCs) and cerebellar nucleus (CN) neurons. In addition, Lc chimeras with the fewest PCs also had numerous reactive microglia and Bergmann glia located in the cerebellar cortex. Structural and functional abnormalities observed in the cerebella of Lc chimeras appeared to be along a continuum, with the degree of pathology related to the number of PCs in individual chimeras.

PMID: 26837618 [PubMed - as supplied by publisher]

Autistic children exhibit decreased levels of essential Fatty acids in red blood cells.

February 4, 2016 - 7:29am
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Autistic children exhibit decreased levels of essential Fatty acids in red blood cells.

Int J Mol Sci. 2015;16(5):10061-76

Authors: Brigandi SA, Shao H, Qian SY, Shen Y, Wu BL, Kang JX

Abstract
Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are essential nutrients for brain development and function. However, whether or not the levels of these fatty acids are altered in individuals with autism remains debatable. In this study, we compared the fatty acid contents between 121 autistic patients and 110 non-autistic, non-developmentally delayed controls, aged 3-17. Analysis of the fatty acid composition of red blood cell (RBC) membrane phospholipids showed that the percentage of total PUFA was lower in autistic patients than in controls; levels of n-6 arachidonic acid (AA) and n-3 docosahexaenoic acid (DHA) were particularly decreased (p<0.001). In addition, plasma levels of the pro-inflammatory AA metabolite prostaglandin E2 (PGE2) were higher in a subset of the autistic participants (n=20) compared to controls. Our study demonstrates an alteration in the PUFA profile and increased production of a PUFA-derived metabolite in autistic patients, supporting the hypothesis that abnormal lipid metabolism is implicated in autism.

PMID: 25946342 [PubMed - indexed for MEDLINE]

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.

February 4, 2016 - 7:29am
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MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.

Eur J Hum Genet. 2015 Jun;23(6):781-9

Authors: Mullegama SV, Pugliesi L, Burns B, Shah Z, Tahir R, Gu Y, Nelson DL, Elsea SH

Abstract
Individuals with autism spectrum disorders (ASD) who have an identifiable single-gene neurodevelopmental disorder (NDD), such as fragile X syndrome (FXS, FMR1), Smith-Magenis syndrome (SMS, RAI1), or 2q23.1 deletion syndrome (del 2q23.1, MBD5) share phenotypic features, including a high prevalence of sleep disturbance. We describe the circadian deficits in del 2q23.1 through caregiver surveys in which we identify several frequent sleep anomalies, including night/early awakenings, coughing/snoring loudly, and difficulty falling asleep. We couple these findings with studies on the molecular analysis of the circadian deficits associated with haploinsufficiency of MBD5 in which circadian gene mRNA levels of NR1D2, PER1, PER2, and PER3 were altered in del 2q23.1 lymphoblastoid cell lines (LCLs), signifying that haploinsufficiency of MBD5 can result in dysregulation of circadian rhythm gene expression. These findings were further supported by expression microarrays of MBD5 siRNA knockdown cells that showed significantly altered expression of additional circadian rhythm signaling pathway genes. Based on the common sleep phenotypes observed in del 2q23.1, SMS, and FXS patients, we explored the possibility that MBD5, RAI1, and FMR1 function in overlapping circadian rhythm pathways. Bioinformatic analysis identified conserved putative E boxes in MBD5 and RAI1, and expression levels of NR1D2 and CRY2 were significantly reduced in patient LCLs. Circadian and mTOR signaling pathways, both associated with sleep disturbance, were altered in both MBD5 and RAI1 knockdown microarray data, overlapping with findings associated with FMR1. These data support phenotypic and molecular overlaps across these syndromes that may be exploited to provide therapeutic intervention for multiple disorders.

PMID: 25271084 [PubMed - indexed for MEDLINE]

Excess of runs of homozygosity is associated with severe cognitive impairment in intellectual disability.

February 4, 2016 - 7:29am
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Excess of runs of homozygosity is associated with severe cognitive impairment in intellectual disability.

Genet Med. 2015 May;17(5):396-9

Authors: Gandin I, Faletra F, Faletra F, Carella M, Pecile V, Ferrero GB, Biamino E, Palumbo P, Palumbo O, Bosco P, Romano C, Belcaro C, Vozzi D, d'Adamo AP

Abstract
PURPOSE: The harmful effects of inbreeding are well known by geneticists, and several studies have already reported cases of intellectual disability caused by recessive variants in consanguineous families. Nevertheless, the effects of inbreeding on the degree of intellectual disability are still poorly investigated. Here, we present a detailed analysis of the homozygosity regions in a cohort of 612 patients with intellectual disabilities of different degrees.
METHODS: We investigated (i) the runs of homozygosity distribution between syndromic and nonsyndromic ID (ii) the effect of runs of homozygosity on the ID degree, using the intelligence quotient score.
RESULTS: Our data revealed no significant differences in the first analysis; instead we detected significantly larger runs of homozygosity stretches in severe ID compared to nonsevere ID cases (P = 0.007), together with an increase of the percentage of genome covered by runs of homozygosity (P = 0.03).
CONCLUSION: In accord with the recent findings regarding autism and other neurological disorders, this study reveals the important role of autosomal recessive variants in intellectual disability. The amount of homozygosity seems to modulate the degree of cognitive impairment despite the intellectual disability cause.

PMID: 25232855 [PubMed - indexed for MEDLINE]

Novel 14q11.2 microduplication including the CHD8 and SUPT16H genes associated with developmental delay.

February 3, 2016 - 7:26am
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Novel 14q11.2 microduplication including the CHD8 and SUPT16H genes associated with developmental delay.

Am J Med Genet A. 2016 Feb 2;

Authors: Smyk M, Poluha A, Jaszczuk I, Bartnik M, Bernaciak J, Nowakowska B

Abstract
Neurodevelopmental disorders have long been associated with chromosomal abnormalities, including microdeletions and microduplications. Submicroscopic 14q11.2 deletions involving the CHD8 and SUPT16H genes have been reported in patients with developmental delay (DD)/intellectual disability (ID) or autism spectrum disorders (ASDs) and/or macrocephaly. Recently, disruptive CHD8 mutations were described in patients with similar phenotypes further showing pivotal role of CHD8 gene in the pathogenesis of DD/ID or ASDs. We report here the first case of ∼445 kb de novo microduplication, encompassing the minimal critical 14q11.2 deletion region, in 8-year-old boy showing DD, cognitive impairment and facial dysmorphism. Our results suggest that gain of the chromosomal region 14q11.2 is causative for clinical findings present in the patient. © 2016 Wiley Periodicals, Inc.

PMID: 26834018 [PubMed - as supplied by publisher]

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

February 3, 2016 - 7:26am
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Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.

Neuron. 2016 Jan 27;

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 - as supplied by publisher]

Autism and Cancer Share Risk Genes, Pathways, and Drug Targets.

February 3, 2016 - 7:26am
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Autism and Cancer Share Risk Genes, Pathways, and Drug Targets.

Trends Genet. 2016 Jan 29;

Authors: Crawley JN, Heyer WD, LaSalle JM

Abstract
Autism is a neurodevelopmental disorder, diagnosed behaviorally by social and communication deficits, repetitive behaviors, and restricted interests. Recent genome-wide exome sequencing has revealed extensive overlap in risk genes for autism and for cancer. Understanding the genetic commonalities of autism(s) and cancer(s), with a focus on mechanistic pathways, could lead to repurposed therapeutics.

PMID: 26830258 [PubMed - as supplied by publisher]

Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors.

February 3, 2016 - 7:26am
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Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors.

Mol Psychiatry. 2016 Feb 2;

Authors: Belinson H, Nakatani J, Babineau BA, Birnbaum RY, Ellegood J, Bershteyn M, McEvilly RJ, Long JM, Willert K, Klein OD, Ahituv N, Lerch JP, Rosenfeld MG, Wynshaw-Boris A

Abstract
Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Disheveled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a β-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the β-catenin/Brn2/Tbr2 transcriptional cascade and the embryonic brain phenotypes. Remarkably, this embryonic treatment prevented adult behavioral deficits and partially rescued abnormal brain structure in Dvl mutant mice. Our findings define a mechanism that links fetal brain development and adult behavior, demonstrating a fetal origin for social and repetitive behavior deficits seen in disorders such as autism.Molecular Psychiatry advance online publication, 2 February 2016; doi:10.1038/mp.2015.207.

PMID: 26830142 [PubMed - as supplied by publisher]

[Sanfilippo Syndrome].

February 3, 2016 - 7:26am
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[Sanfilippo Syndrome].

Vestn Ross Akad Med Nauk. 2015;(4):419-27

Authors: Osipova LA, Kuzenkova LM, Namazova-Baranova LS, Gevorkyan AK, Podkletnova TV, Vashakmadze ND

Abstract
Sanfilippo syndrome (mucopolysaccharidosis type III) is a lysosomal disorder caused by a defect in the catabolism of heparan sulfate. Mucopolysaccharidosis type III is the most common type of all mucopolysaccharidoses. The pathogenic basis of the disease consists of the storage of undegraded substrate in the central nervous system. Progressive cognitive decline resulting in dementia and behavioural abnormalities are the main clinical characteristics of Sanfilippo syndrome. Mucopolysaccharidosis type III may be misdiagnosed as otherforms of developmental delay, attention deficit/hyperactivity disorder and autistic spectrum disorders because of lack of somatic symptoms, presence of mild and atypical forms of the disease. Patients with Sanfilippo syndrome may have comparatively low urinary glycosaminoglycans levels resulting in false negative urinary assay. Definitive diagnosis is made by enzyme assay on leucocytes and cultured fibroblasts. There is currently no effective treatment of mucopolysaccharidosis type III, though ongoing researches of gene, substrate reduction and intrathecal enzyme replacement therapies expect getting curative method to alter devasting damage of central nervous system in near future.

PMID: 26710524 [PubMed - indexed for MEDLINE]

Selective Dysregulation of Hippocampal Inhibition in the Mouse Lacking Autism Candidate Gene CNTNAP2.

February 3, 2016 - 7:26am
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Selective Dysregulation of Hippocampal Inhibition in the Mouse Lacking Autism Candidate Gene CNTNAP2.

J Neurosci. 2015 Oct 28;35(43):14681-7

Authors: Jurgensen S, Castillo PE

Abstract
Mutations in the human gene encoding contactin-associated protein-like 2 (CNTNAP2) have been strongly associated with autism spectrum disorders (ASDs). Cntnap2(-/-) mice recapitulate major features of ASD, including social impairment, reduced vocalizations, and repetitive behavior. In addition, Cntnap2(-/-) mice show reduced cortical neuronal synchrony and develop spontaneous seizures throughout adulthood. As suggested for other forms of ASDs, this phenotype could reflect some form of synaptic dysregulation. However, the impact of lifelong deletion of CNTNAP2 on synaptic function in the brain remains unknown. To address this issue, we have assessed excitatory and inhibitory synaptic transmission in acute hippocampal slices of Cntnap2(-/-) mice. We found that although excitatory transmission was mostly normal, inhibition onto CA1 pyramidal cells was altered in Cntnap2(-/-) mice. Specifically, putative perisomatic, but not dendritic, evoked IPSCs were significantly reduced in these mice. Whereas both inhibitory short-term plasticity and miniature IPSC frequency and amplitude were normal in Cntnap2(-/-) mice, we found an unexpected increase in the frequency of spontaneous, action potential-driven IPSCs. Altered hippocampal inhibition could account for the behavioral phenotype Cntnap2(-/-) mice present later in life. Overall, our findings that Cntnap2 deletion selectively impairs perisomatic hippocampal inhibition while sparing excitation provide additional support for synaptic dysfunction as a common mechanism underlying ASDs.

PMID: 26511255 [PubMed - indexed for MEDLINE]

Enhanced synapse remodelling as a common phenotype in mouse models of autism.

February 3, 2016 - 7:26am
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Enhanced synapse remodelling as a common phenotype in mouse models of autism.

Nat Commun. 2014;5:4742

Authors: Isshiki M, Tanaka S, Kuriu T, Tabuchi K, Takumi T, Okabe S

Abstract
Developmental deficits in neuronal connectivity are considered to be present in patients with autism spectrum disorders (ASDs). Here we examine this possibility by using in vivo spine imaging in the early postnatal cortex of ASD mouse models. Spines are classified by the presence of either the excitatory postsynaptic marker PSD-95 or the inhibitory postsynaptic marker gephyrin. ASD mouse models show consistent upregulation in the dynamics of PSD-95-positive spines, which may subsequently contribute to stable synaptic connectivity. In contrast, spines receiving inputs from the thalamus, detected by the presence of gephyrin clusters, are larger, highly stable and unaffected in ASD mouse models. Importantly, two distinct mouse models, human 15q11-13 duplication and neuroligin-3 R451C point mutation, show highly similar phenotypes in spine dynamics. This selective impairment in dynamics of PSD-95-positive spines receiving intracortical projections may be a core component of early pathological changes and be a potential target of early intervention.

PMID: 25144834 [PubMed - indexed for MEDLINE]

Carnitine transport and fatty acid oxidation.

February 2, 2016 - 7:23am

Carnitine transport and fatty acid oxidation.

Biochim Biophys Acta. 2016 Jan 29;

Authors: Longo N, Frigeni M, Pasquali M

Abstract
Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. It can be synthesized by the body or assumed with the diet from meat and dairy products. Defects in carnitine biosynthesis do not routinely result in low plasma carnitine levels. Carnitine is accumulated by the cells and retained by kidneys using OCTN2, a high affinity organic cation transporter specific for carnitine. Defects in the OCTN2 carnitine transporter results in autosomal recessive primary carnitine deficiency characterized by decreased intracellular carnitine accumulation, increased losses of carnitine in the urine, and low serum carnitine levels. Patients can present early in life with hypoketotic hypoglycemia and hepatic encephalopathy, or later in life with skeletal and cardiac myopathy or sudden death from cardiac arrhythmia, usually triggered by fasting or catabolic state. This disease responds to oral carnitine that, in pharmacological doses, enters cells using the amino acid transporter B(0,+). Primary carnitine deficiency can be suspected from the clinical presentation or identified by low levels of free carnitine (C0) in the newborn screening. Some adult patients have been diagnosed following the birth of an unaffected child with very low carnitine levels in the newborn screening. The diagnosis is confirmed by measuring low carnitine uptake in the patients' fibroblasts or by DNA sequencing of the SLC22A5 gene encoding the OCTN2 carnitine transporter. Some mutations are specific for certain ethnic backgrounds, but the majority are private and identified only in individual families. Although the genotype usually does not correlate with metabolic or cardiac involvement in primary carnitine deficiency, patients presenting as adults tend to have at least one missense mutation retaining residual activity.

PMID: 26828774 [PubMed - as supplied by publisher]

Inherited PTEN mutations and the prediction of phenotype.

February 2, 2016 - 7:23am

Inherited PTEN mutations and the prediction of phenotype.

Semin Cell Dev Biol. 2016 Jan 28;

Authors: Leslie NR, Longy M

Abstract
PTEN has been heavily studied due to its role as a tumour suppressor and as a core inhibitory component of the phosphoinositide 3-kinase (PI3K) signalling network. It is a broadly expressed phosphatase which displays complexity and diversity in both its functions and regulation and accordingly, in the laboratory numerous classes of functionally distinct mutations have been generated. Inherited loss of function mutations in the PTEN gene were originally identified in sufferers of Cowden disease, but later shown to associate with more diverse human pathologies, mostly relating to cell and tissue overgrowth, leading to the use of the broader term, PTEN Hamartoma Tumour Syndrome. Recent phenotypic analysis of clinical cohorts of PTEN mutation carriers, combined with laboratory studies of the consequences of these mutations implies that stable catalytically inactive PTEN mutants may lead to the most severe phenotypes, and conversely, that mutants retaining partial function associate more frequently with a milder phenotype, with autism spectrum disorder often being diagnosed. Future work will be needed to confirm and to refine these genotype-phenotype relationships and convert this developing knowledge into improved patient management and potentially treatment with emerging drugs which target the PI3K pathway.

PMID: 26827793 [PubMed - as supplied by publisher]

Identification and Functional Characterization of a Novel CACNA1C-Mediated Cardiac Disorder Characterized by Prolonged QT Intervals With Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death.

February 2, 2016 - 7:23am
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Identification and Functional Characterization of a Novel CACNA1C-Mediated Cardiac Disorder Characterized by Prolonged QT Intervals With Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death.

Circ Arrhythm Electrophysiol. 2015 Oct;8(5):1122-32

Authors: Boczek NJ, Ye D, Jin F, Tester DJ, Huseby A, Bos JM, Johnson AJ, Kanter R, Ackerman MJ

Abstract
BACKGROUND: A portion of sudden cardiac deaths can be attributed to structural heart diseases, such as hypertrophic cardiomyopathy (HCM) or cardiac channelopathies such as long-QT syndrome (LQTS); however, the underlying molecular mechanisms are distinct. Here, we identify a novel CACNA1C missense mutation with mixed loss-of-function/gain-of-function responsible for a complex phenotype of LQTS, HCM, sudden cardiac death, and congenital heart defects.
METHODS AND RESULTS: Whole exome sequencing in combination with Ingenuity variant analysis was completed on 3 affected individuals and 1 unaffected individual from a large pedigree with concomitant LQTS, HCM, and congenital heart defects and identified a novel CACNA1C mutation, p.Arg518Cys, as the most likely candidate mutation. Mutational analysis of exon 12 of CACNA1C was completed on 5 additional patients with a similar phenotype of LQTS plus a personal or family history of HCM-like phenotypes and identified 2 additional pedigrees with mutations at the same position, p.Arg518Cys/His. Whole cell patch clamp technique was used to assess the electrophysiological effects of the identified mutations in CaV1.2 and revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current.
CONCLUSIONS: Through whole exome sequencing and expanded cohort screening, we identified a novel genetic substrate p.Arg518Cys/His-CACNA1C, in patients with a complex phenotype including LQTS, HCM, and congenital heart defects annotated as cardiac-only Timothy syndrome. Our electrophysiological studies, identification of mutations at the same amino acid position in multiple pedigrees, and cosegregation with disease in these pedigrees provide evidence that p.Arg518Cys/His is the pathogenic substrate for the observed phenotype.

PMID: 26253506 [PubMed - indexed for MEDLINE]

The RNA-binding protein Rbfox1 regulates splicing required for skeletal muscle structure and function.

February 2, 2016 - 7:23am
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The RNA-binding protein Rbfox1 regulates splicing required for skeletal muscle structure and function.

Hum Mol Genet. 2015 Apr 15;24(8):2360-74

Authors: Pedrotti S, Giudice J, Dagnino-Acosta A, Knoblauch M, Singh RK, Hanna A, Mo Q, Hicks J, Hamilton S, Cooper TA

Abstract
The Rbfox family of RNA-binding proteins is highly conserved with established roles in alternative splicing (AS) regulation. High-throughput studies aimed at understanding transcriptome remodeling have revealed skeletal muscle as displaying one of the largest number of AS events. This finding is consistent with requirements for tissue-specific protein isoforms needed to sustain muscle-specific functions. Rbfox1 is abundant in vertebrate brain, heart and skeletal muscle. Genome-wide genetic approaches have linked the Rbfox1 gene to autism, and a brain-specific knockout mouse revealed a critical role for this splicing regulator in neuronal function. Moreover, a Caenorhabditis elegans Rbfox1 homolog regulates muscle-specific splicing. To determine the role of Rbfox1 in muscle function, we developed a conditional knockout mouse model to specifically delete Rbfox1 in adult tissue. We show that Rbfox1 is required for muscle function but a >70% loss of Rbfox1 in satellite cells does not disrupt muscle regeneration. Deep sequencing identified aberrant splicing of multiple genes including those encoding myofibrillar and cytoskeletal proteins, and proteins that regulate calcium handling. Ultrastructure analysis of Rbfox1(-/-) muscle by electron microscopy revealed abundant tubular aggregates. Immunostaining showed mislocalization of the sarcoplasmic reticulum proteins Serca1 and Ryr1 in a pattern indicative of colocalization with the tubular aggregates. Consistent with mislocalization of Serca1 and Ryr1, calcium handling was drastically altered in Rbfox1(-/-) muscle. Moreover, muscle function was significantly impaired in Rbfox1(-/-) muscle as indicated by decreased force generation. These results demonstrate that Rbfox1 regulates a network of AS events required to maintain multiple aspects of muscle physiology.

PMID: 25575511 [PubMed - indexed for MEDLINE]

Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits.

January 31, 2016 - 7:17am

Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits.

Cereb Cortex. 2016 Jan 29;

Authors: Oaks AW, Zamarbide M, Tambunan DE, Santini E, Di Costanzo S, Pond HL, Johnson MW, Lin J, Gonzalez DM, Boehler JF, Wu GK, Klann E, Walsh CA, Manzini MC

Abstract
Loss-of-function (LOF) mutations in CC2D1A cause a spectrum of neurodevelopmental disorders, including intellectual disability, autism spectrum disorder, and seizures, identifying a critical role for this gene in cognitive and social development. CC2D1A regulates intracellular signaling processes that are critical for neuronal function, but previous attempts to model the human LOF phenotypes have been prevented by perinatal lethality in Cc2d1a-deficient mice. To overcome this challenge, we generated a floxed Cc2d1a allele for conditional removal of Cc2d1a in the brain using Cre recombinase. While removal of Cc2d1a in neuronal progenitors using Cre expressed from the Nestin promoter still causes death at birth, conditional postnatal removal of Cc2d1a in the forebrain via calcium/calmodulin-dependent protein kinase II-alpha (CamKIIa) promoter-driven Cre generates animals that are viable and fertile with grossly normal anatomy. Analysis of neuronal morphology identified abnormal cortical dendrite organization and a reduction in dendritic spine density. These animals display deficits in neuronal plasticity and in spatial learning and memory that are accompanied by reduced sociability, hyperactivity, anxiety, and excessive grooming. Cc2d1a conditional knockout mice therefore recapitulate features of both cognitive and social impairment caused by human CC2D1A mutation, and represent a model that could provide much needed insights into the developmental mechanisms underlying nonsyndromic neurodevelopmental disorders.

PMID: 26826102 [PubMed - as supplied by publisher]

Neuropsychological phenotype and psychopathology in seven adult patients with Phelan-McDermid syndrome: Implications for treatment strategy.

January 30, 2016 - 6:26am

Neuropsychological phenotype and psychopathology in seven adult patients with Phelan-McDermid syndrome: Implications for treatment strategy.

Genes Brain Behav. 2016 Jan 29;

Authors: Egger JI, Zwanenburg RJ, van Ravenswaaij-Arts CM, Kleefstra T, Verhoeven WM

Abstract
Phelan-McDermid syndrome or 22q13.3 deletion syndrome is characterized by a variable degree of intellectual disability, impaired speech and language as well as social communicative skills, and mild dysmorphic features. The SHANK3 gene is thought to be a major contributor to the phenotype. Apart from the syndrome associated autistic features, symptoms from the bipolar spectrum can be discerned, in particular behaviour instability and fluctuating mood culminating in a (hypo)manic state. In case of coincident major somatic events, a deteriorating course may occur. The present study comprises seven adult patients (four females, three males; aged 21-44 years) with genetically proven Phelan-McDermid syndrome. Data from medical records were collected and extensive assessment of neuropsychological variables was performed to identify cognitive characteristics and their relation with psychopathology and treatment. All patients showed profound communication deficits and their developmental functioning ranged from 1,0 to 6,3 years. In addition, they had slow speed of information processing, impairment of attentional and executive functions, and cognitive alexithymia. As to psychopathology, features from the affective and anxiety domains were prominent findings in these seven patients suggesting the presence of a bipolar spectrum disorder, that could be effectively moderated with mood stabilizing agents. Results are discussed in terms of the putative involvement of structural brain abnormalities, in particular cerebellar vermis hypoplasia and corpus callosum thinning and their cognitive and emotional sequellae. It is concluded that treatment of 22q13.3 associated psychopathology should include prescription of mood stabilizing agents in combination with individually tailored contextual neuropsychological measures.

PMID: 26824576 [PubMed - as supplied by publisher]

The maternal interleukin-17a pathway in mice promotes autismlike phenotypes in offspring.

January 30, 2016 - 6:26am

The maternal interleukin-17a pathway in mice promotes autismlike phenotypes in offspring.

Science. 2016 Jan 28;

Authors: Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim SV, Hoeffer CA, Littman DR, Huh JR

Abstract
Viral infection during pregnancy has been correlated with increased frequency of autism spectrum disorder (ASD) in offspring. This observation has been modeled in rodents subjected to maternal immune activation (MIA). The immune cell populations critical in the MIA model have not been identified. Using both genetic mutants and blocking antibodies in mice, we show that retinoic acid receptor-related orphan nuclear receptor γt (RORγt)-dependent effector T lymphocytes [e.g., T helper 17 (TH17) cells] and the effector cytokine interleukin-17a (IL-17a) are required in mothers for MIA-induced behavioral abnormalities in offspring. We find that MIA induces an abnormal cortical phenotype, which is also dependent on maternal IL-17a, in the fetal brain. Our data suggest that therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce the likelihood of bearing children with inflammation-induced ASD-like phenotypes.

PMID: 26822608 [PubMed - as supplied by publisher]

Altered Microglia in the Amygdala Are Involved in Anxiety-related Behaviors of a Copy Number Variation Mouse Model of Autism.

January 30, 2016 - 6:26am
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Altered Microglia in the Amygdala Are Involved in Anxiety-related Behaviors of a Copy Number Variation Mouse Model of Autism.

J Nippon Med Sch. 2015;82(2):92-9

Authors: Shigemori T, Sakai A, Takumi T, Itoh Y, Suzuki H

Abstract
BACKGROUND AND PURPOSE: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic basis. Although anxiety is a common major psychiatric condition in ASD, the underlying mechanisms of the anxiety are poorly understood. In individuals with ASD, evidence indicates a structural abnormality in the amygdala, a key component involved in anxiety and social behavior. Microglia, which are central nervous system-resident immune cells implicated in neurodevelopmental processes, are also reportedly altered in ASD. In the present study, we examined the involvement of microglia in the anxiety-related behaviors of ASD model mouse.
METHODS: Mice that have a 6.3-Mb paternal duplication (patDp/+) corresponding to human chromosome 15q11-q13 were used as an ASD model. Iba1, a microglial activation marker, was examined in the amygdala using immunofluorescence. Effects of perinatal treatment with minocycline, a microglial modulator, on anxiety-related behaviors were examined in neonatal and adolescent patDp/+ mice.
RESULTS: In patDp/+ mice, Iba1 was decreased in the basolateral amygdala at postnatal day 7, but not at postnatal days 37-40. Perinatal treatment with minocycline restored the Iba1 expression and reduced anxiety-related behaviors in patDp/+ adolescent mice.
CONCLUSIONS: Perinatal microglia in the basolateral amygdala may play a pathogenic role in the anxiety observed in a mouse model of ASD with duplication of human chromosome 15q11-q13.

PMID: 25959200 [PubMed - indexed for MEDLINE]

Universal Autism Screening for Toddlers: Recommendations at Odds.

January 29, 2016 - 8:54am

Universal Autism Screening for Toddlers: Recommendations at Odds.

J Autism Dev Disord. 2016 Jan 28;

Authors: Robins DL, Adamson LB, Barton M, Connell JE, Dumont-Mathieu T, Dworkin PH, Fein D, Greenstein MA, Hsu HW, Kerns C, Newschaffer C, Plumb J, Shattuck P, Turchi R, Vivanti G

PMID: 26820633 [PubMed - as supplied by publisher]

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