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

Kreilaus, Fabian; Chesworth, Rose; Eapen, Valsamma; Clarke, Raymond A.; Karl, Tim

doi:10.1016/j.bbr.2019.112057

Cited by 19 publications

(34 citation statements)

References 64 publications

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“…Fabian et al recently conducted an animal-based study using IMMP2L knockdown mice to study the effect of IMMP2L deficiency on behavioral domains. This study shows that IMMP2L deficiency induced behavioral effects, which was gene-dose and sex dependent [134]. However, IMMP2L may be not a common gene that causes ASD because coding mutation was not observed in ASD patients [135].…”

Section: Immp2lmentioning

confidence: 75%

Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder

Yoon

Choi

Lee

et al. 2020

JCM

107

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Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by difficulties in social interaction, language development delays, repeated body movements, and markedly deteriorated activities and interests. Environmental factors, such as viral infection, parental age, and zinc deficiency, can be plausible contributors to ASD susceptibility. As ASD is highly heritable, genetic risk factors involved in neurodevelopment, neural communication, and social interaction provide important clues in explaining the etiology of ASD. Accumulated evidence also shows an important role of epigenetic factors, such as DNA methylation, histone modification, and noncoding RNA, in ASD etiology. In this review, we compiled the research published to date and described the genetic and epigenetic epidemiology together with environmental risk factors underlying the etiology of the different phenotypes of ASD.

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Section: Immp2lmentioning

confidence: 75%

Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder

Yoon

Choi

Lee

et al. 2020

JCM

107

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“…In this study, PEN-SCZ patients I and II, who carried deletions in IMMP2L exons 1-3, presented with additional autistic features, including limited social communication skills in addition to psychosis (Table 2). Interestingly, a previous animal study demonstrated that IMMP2L knockout mice displayed behavioral changes in social interactions linked to both limited social PLOS ONE skills in ASD and negative symptoms in SCZ [33]. Limited social skills in ASD may be broadly linked to negative symptoms in SCZ, in terms of their biological aspects associated with possibly impaired IMMP2L function.…”

Section: Clinical Characteristics Of Immp2l Deletion Carriers In Pen-sczmentioning

confidence: 98%

Exonic deletions in IMMP2L in schizophrenia with enhanced glycation stress subtype

Yoshikawa

Kushima²,

Miyashita³

et al. 2022

PLoS ONE

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We previously identified a subtype of schizophrenia (SCZ) characterized by increased plasma pentosidine, a marker of glycation and oxidative stress (PEN-SCZ). However, the genetic factors associated with PEN-SCZ have not been fully clarified. We performed a genome-wide copy number variation (CNV) analysis to identify CNVs associated with PEN-SCZ to provide an insight into the novel therapeutic targets for PEN-SCZ. Plasma pentosidine was measured by high-performance liquid chromatography in 185 patients with SCZ harboring rare CNVs detected by array comparative genomic hybridization. In three patients with PEN-SCZ showing additional autistic features, we detected a novel deletion at 7q31.1 within exons 2 and 3 of IMMP2L, which encodes the inner mitochondrial membrane peptidase subunit 2. The deletion was neither observed in non-PEN-SCZ nor in public database of control subjects. IMMP2L is one of the SCZ risk loci genes identified in a previous SCZ genome-wide association study, and its trans-populational association was recently described. Interestingly, deletions in IMMP2L have been previously linked with autism spectrum disorder. Disrupted IMMP2L function has been shown to cause glycation/oxidative stress in neuronal cells in an age-dependent manner. To our knowledge, this is the first genome-wide CNV study to suggest the involvement of IMMP2L exons 2 and 3 in the etiology of PEN-SCZ. The combination of genomic information with plasma pentosidine levels may contribute to the classification of biological SCZ subtypes that show additional autistic features. Modifying IMMP2L functions may be useful for treating PEN-SCZ if the underlying biological mechanism can be clarified in further studies.

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“…In addition, IMMP2L has demonstrated haplotype sharing in multiple ASD populations and deleterious exon deletions have been identified in ASD individuals and families (22,52,65,66,71,74,177) at significantly higher frequency than in control populations. Furthermore, reducing Immp2l dose in mice causes behavioral changes relevant to GTS behavioral deficits (85).…”

Section: Optimisation Of Mitochondrial Supplymentioning

confidence: 99%

Tourette Syndrome Risk Genes Regulate Mitochondrial Dynamics, Structure, and Function

2021

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Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by motor and vocal tics with an estimated prevalence of 1% in children and adolescents. GTS has high rates of inheritance with many rare mutations identified. Apart from the role of the neurexin trans-synaptic connexus (NTSC) little has been confirmed regarding the molecular basis of GTS. The NTSC pathway regulates neuronal circuitry development, synaptic connectivity and neurotransmission. In this study we integrate GTS mutations into mitochondrial pathways that also regulate neuronal circuitry development, synaptic connectivity and neurotransmission. Many deleterious mutations in GTS occur in genes with complementary and consecutive roles in mitochondrial dynamics, structure and function (MDSF) pathways. These genes include those involved in mitochondrial transport (NDE1, DISC1, OPA1), mitochondrial fusion (OPA1), fission (ADCY2, DGKB, AMPK/PKA, RCAN1, PKC), mitochondrial metabolic and bio-energetic optimization (IMMP2L, MPV17, MRPL3, MRPL44). This study is the first to develop and describe an integrated mitochondrial pathway in the pathogenesis of GTS. The evidence from this study and our earlier modeling of GTS molecular pathways provides compounding support for a GTS deficit in mitochondrial supply affecting neurotransmission.

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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

Cited by 19 publications

References 64 publications

Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder

Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder

Exonic deletions in IMMP2L in schizophrenia with enhanced glycation stress subtype

Tourette Syndrome Risk Genes Regulate Mitochondrial Dynamics, Structure, and Function

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