Developmental Pleiotropy of PTEN in Congenital Hydrocephalus and Autism Spectrum Disorder

Abstract INTRODUCTION A population-based study has found that approximately one quarter of individuals diagnosed with congenital hydrocephalus (CH) are also diagnosed with autism spectrum disorder (ASD); however, a common mechanism underlying these seemingly disparate disorders is unknown. We hypothesize that rare, damaging mutations in genes cause a pleiotropic effect responsible for the development of both CH and ASD. METHODS Using WES studies >250 CH patients, we selected 42 DNMs in genes with the greatest probability of loss-of-function (LoF) (pLI > .9), to determine whether there was an enrichment of ASD genes (pLI > .9) found in denovo-db, a national database of ASD DNMs A 2 × 2 contingency table revealed a 2.18-fold enrichment of ASD genes in sporadic CH genes (P-value = . 011). Gene Ontology analysis found >100-fold enrichment of TORC1 signaling (GO: 0031931) as a significantly enriched module (P-value = .000152). We recapitulated the CH phenotype in a genetic mouse model; wherein, Pten, a direct negative regulator of torc1 signaling, is conditionally knocked-out (Pten cKO) in a select subset of NSCs previously associated with an ASD phenotype in mice. Kaplan-Meier survival curves were constructed for Pten cKO and their WT, control littermates. Rapamycin was injected intraperitoneally in Pten cKO and WT mice daily from postnatal (P) days 10 to 22. RESULTS Pten cKO resulted in fully penetrant, fatal hydrocephalus with a median survival of P17.5. WT mice (n = 41) survived significantly longer than Pten cKO mice (n = 10) (P < .0001). Rapamycin rescued the fatal hydrocephalus phenotype (n = 8) by inhibition of mTOR (P < .0001). CONCLUSION PTEN mutations have previously been identified in ASD patients. Here, we present statistical analyses and a mouse model to support our hypothesis that ASD diagnoses in some CH patients may be a neurodevelopmental sequelae of PTEN LoF. These findings suggest that early ASD service interventions may benefit a subset of CH patients who would otherwise be managed solely with surgery.

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First behavioural assessment of a novel Immp2l knockdown mouse model with relevance for Gilles de la Tourette syndrome and Autism spectrum disorder

Behavioural Brain Research ◽

10.1016/j.bbr.2019.112057 ◽

2019 ◽

Vol 374 ◽

pp. 112057 ◽

Cited By ~ 1

Author(s):

Fabian Kreilaus ◽

Rose Chesworth ◽

Valsamma Eapen ◽

Raymond Clarke ◽

Tim Karl

Keyword(s):

Autism Spectrum Disorder ◽

Mouse Model ◽

Tourette Syndrome ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Behavioural Assessment

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Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

Molecular Brain ◽

10.1186/s13041-021-00769-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Kohei Kitagawa ◽

Kensuke Matsumura ◽

Masayuki Baba ◽

Momoka Kondo ◽

Tomoya Takemoto ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Behavior ◽

Mouse Model ◽

Mouse Models ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

De Novo Mutation ◽

Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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Behavioral phenotypes and neurobiological mechanisms in the Shank1 mouse model for autism spectrum disorder: A translational perspective

Behavioural Brain Research ◽

10.1016/j.bbr.2017.09.038 ◽

2018 ◽

Vol 352 ◽

pp. 46-61 ◽

Cited By ~ 12

Author(s):

A. Özge Sungur ◽

Rainer K.W. Schwarting ◽

Markus Wöhr

Keyword(s):

Autism Spectrum Disorder ◽

Mouse Model ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Behavioral Phenotypes

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High Resolution Magnetic Resonance Imaging for Characterization of the Neuroligin-3 Knock-in Mouse Model Associated with Autism Spectrum Disorder

PLoS ONE ◽

10.1371/journal.pone.0109872 ◽

2014 ◽

Vol 9 (10) ◽

pp. e109872 ◽

Cited By ~ 18

Author(s):

Manoj Kumar ◽

Jeffery T. Duda ◽

Wei-Ting Hwang ◽

Charles Kenworthy ◽

Ranjit Ittyerah ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Autism Spectrum Disorder ◽

Magnetic Resonance ◽

High Resolution ◽

Mouse Model ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Resonance Imaging

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Mitochondrial Dysfunction in Early Diagnosed Autism Spectrum Disorder Children

Journal of Dhaka Medical College ◽

10.3329/jdmc.v26i1.34000 ◽

2017 ◽

Vol 26 (1) ◽

pp. 43-47 ◽

Cited By ~ 3

Author(s):

Shorifa Shahjadi ◽

Arif Salam Khan ◽

Mesbah Uddin Ahmed

Keyword(s):

Autism Spectrum Disorder ◽

Mitochondrial Dysfunction ◽

Venous Blood ◽

Autism Spectrum ◽

Serum Lactate ◽

Spectrum Disorder ◽

Control Group ◽

P Value ◽

Blood Ammonia ◽

Normal Children

Background: Mitochondrial dysfunction and abnormal brain bioenergetics can cause autism.Cellular function impairment due to mitochondrial dysfunction may cause cognitive impairment, language deficits and abnormal energy metabolism in autism.Objective: The aim of this study was to evaluate biochemical evidence of the mitochondrial dysfunction by measuring blood ammonia, serum lactate, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine kinase (CK) in autism spectrum disorder children.Methods: This observational type of analytical study with case-control design was conducted in the Department of Physiology of Bangabandhu Sheikh Mujib Medical University (BSMMU), Shahbag, Dhaka. For this study, a total number of 20 Subjects were randomly selected, among which 10 were apparently healthy subjects (control group-A) for comparison and 10 were diagnosed children with autism spectrum disorder (study group-B). 5ml venous blood was collected from both groups for analysis serum CK, AST, ALT, lactate and blood ammonia. Blood ammonia, serum lactate, AST, ALT and CK level were estimated in all children by standard laboratory method. Independent samplet test was used for statistical analysis. P value <0.05 was accepted as significant. The mean of all the measured biochemical variables in normal children were within normal ranges.Result: Blood ammonia, serum lactate, AST, CK were found significantly higher in autism spectrum disorder children in comparison to control Conclusion: From the result of this study it may be concluded that mitochondrial dysfunction occur in autistic spectrum disorder children .J Dhaka Medical College, Vol. 26, No.1, April, 2017, Page 43-47

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Mouse Model Systems of Autism Spectrum Disorder: Replicability and Informatics Signature

10.1101/561233 ◽

2019 ◽

Author(s):

Patricia Kabitzke ◽

Diana Morales ◽

Dansha He ◽

Kimberly Cox ◽

Jane Sutphen ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Behavior ◽

Mouse Model ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Model Systems ◽

Activity Levels ◽

Phenotypic Differences ◽

Genetic Mouse Model ◽

Unitary Concept

3.AbstractBackgroundPhenotyping mouse model systems of human disease has proven to be a difficult task, with frequent poor inter- and intra-laboratory replicability and translatability, particularly in behavioral domains such as social and verbal function. However, establishing robust animal model systems with strong construct validity is of fundamental importance as they are central tools for understanding disease pathophysiology and developing therapeutics. To complete our studies of mouse model systems relevant to autism spectrum disorder (ASD), we present a replication of the main findings from our two published studies comprising five genetic mouse model systems of ASD.MethodsTo assess the robustness of our previous results, we chose the two model systems that showed the greatest phenotypic differences, the Shank3/F and Cntnap2, and repeated assessments of general health, activity, and social behavior. We additionally explored all five model systems in the same framework, comparing all results obtained in this three-yearlong effort using informatics techniques to look for commonalities and differences.ResultsResults in the current study were very similar to our previously published results. The informatics signatures of the two model systems chosen for the replication showed that they were most distinguished by activity levels. Although the two model systems were opposite in this regard, those aspects of their social behavior not confounded by activity (vocalizations) were similar.ConclusionsOur results showed high intra-laboratory replicability of results, even for those with effect sizes that were not particularly large, suggesting that discrepancies in the literature may be dependent on subtle differences in testing conditions, housing enrichment, or background strains and not so much on the variability of the behavioral phenotypes. The overall informatics analysis suggests two main classes of model systems that in some aspects lie on opposite ends of the behavioral spectrum, supporting the view that autism is not a unitary concept.

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