Extensive phenotyping of two ARX polyalanine expansion mutation mouse models that span clinical spectrum of intellectual disability and epilepsy

Jackson, Matilda R.; Lee, Kristie; Mattiske, Tessa; Jaehne, Emily J.; Öztürk, Ezgi; Baune, Bernhard T.; O’Brien, Terence J.; Jones, Nigel C.; Shoubridge, Cheryl

doi:10.1016/j.nbd.2017.05.012

Cited by 8 publications

(6 citation statements)

References 54 publications

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“…We describe here the characterization of a new mouse model partially humanized for the ARX c.428_451dup24 duplication, leading to polyalanine expansion in ARX tract 2. Our mouse model supports previous findings showing that this mutation causes a decreased expression of Arx ( 23 , 27 , 38 ). It has been shown that polyalanine expansions cause inappropriate oligomerization of the protein, which is targeted for clearance by the cellular quality-control machinery ( 24 , 39 ), thus possibly explaining the decreased amount of ARX protein that we observed both in western blot ( Fig.…”

Section: Discussionsupporting

confidence: 92%

“…Those results are in agreement with what has been reported for human patients presenting ARX c.428_451dup24 mutations who are described as less severely affected than patients with ARX c.304ins(GCG)7 expansion ( 28 , 42 , 43 ). Another mouse model for ARX c.428_451dup24 mutation has been recently described with much more pronounced spontaneous seizures activity than our model ( 38 ). This difference may be due to a different environmental condition affecting the animals.…”

Section: Discussionmentioning

confidence: 75%

“…This model was generated by Kitamura et al . ( 23 ) on 129SV ES cells and then bred on C57BL/6J (B6J) and backcrossed on C57BL/6NHsd (B6NHsd) genetic background in Jackson’s publication ( 38 ). The only difference with our model is that the latter was backcrossed on B6NTac genetic background.…”

Section: Discussionmentioning

confidence: 99%

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A new mouse model of ARX dup24 recapitulates the patients’ behavioral and fine motor alterations

Dubos

Méziane

Iacono

et al. 2018

Human Molecular Genetics

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The aristaless-related homeobox (ARX) transcription factor is involved in the development of GABAergic and cholinergic neurons in the forebrain. ARX mutations have been associated with a wide spectrum of neurodevelopmental disorders in humans, among which the most frequent, a 24 bp duplication in the polyalanine tract 2 (c.428_451dup24), gives rise to intellectual disability, fine motor defects with or without epilepsy. To understand the functional consequences of this mutation, we generated a partially humanized mouse model carrying the c.428_451dup24 duplication (Arxdup24/0) that we characterized at the behavior, neurological and molecular level. Arxdup24/0 males presented with hyperactivity, enhanced stereotypies and altered contextual fear memory. In addition, Arxdup24/0 males had fine motor defects with alteration of reaching and grasping abilities. Transcriptome analysis of Arxdup24/0 forebrains at E15.5 showed a down-regulation of genes specific to interneurons and an up-regulation of genes normally not expressed in this cell type, suggesting abnormal interneuron development. Accordingly, interneuron migration was altered in the cortex and striatum between E15.5 and P0 with consequences in adults, illustrated by the defect in the inhibitory/excitatory balance in Arxdup24/0 basolateral amygdala. Altogether, we showed that the c.428_451dup24 mutation disrupts Arx function with a direct consequence on interneuron development, leading to hyperactivity and defects in precise motor movement control and associative memory. Interestingly, we highlighted striking similarities between the mouse phenotype and a cohort of 33 male patients with ARX c.428_451dup24, suggesting that this new mutant mouse line is a good model for understanding the pathophysiology and evaluation of treatment.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 75%

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A new mouse model of ARX dup24 recapitulates the patients’ behavioral and fine motor alterations

Dubos

Méziane

Iacono

et al. 2018

Human Molecular Genetics

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“…Iqsec2 KO heterozygous and wild-type females underwent monthly behavioural testing from one to 6 mo of age (n = 4 Iqsec2 KO heterozygous and n = 3 wild-type controls at 1 mo, n = 8 Iqsec2 KO heterozygous, and n = 6 wild-type controls at all other time points) as previously described (25).…”

Section: Methodsmentioning

confidence: 99%

Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females

et al. 2019

Self Cite

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Clinical presentations of mutations in the IQSEC2 gene on the X-chromosome initially implicated to cause non-syndromic intellectual disability (ID) in males have expanded to include early onset seizures in males as well as in females. The molecular pathogenesis is not well understood, nor the mechanisms driving disease expression in heterozygous females. Using a CRISPR/Cas9–edited Iqsec2 KO mouse model, we confirm the loss of Iqsec2 mRNA expression and lack of Iqsec2 protein within the brain of both founder and progeny mice. Both male (52%) and female (46%) Iqsec2 KO mice present with frequent and recurrent seizures. Focusing on Iqsec2 KO heterozygous female mice, we demonstrate increased hyperactivity, altered anxiety and fear responses, decreased social interactions, delayed learning capacity and decreased memory retention/novel recognition, recapitulating psychiatric issues, autistic-like features, and cognitive deficits present in female patients with loss-of-function IQSEC2 variants. Despite Iqsec2 normally acting to activate Arf6 substrate, we demonstrate that mice modelling the loss of Iqsec2 function present with increased levels of activated Arf6. We contend that loss of Iqsec2 function leads to altered regulation of activated Arf6-mediated responses to synaptic signalling and immature synaptic networks. We highlight the importance of IQSEC2 function for females by reporting a novel nonsense variant c.566C > A, p.(S189*) in an elderly female patient with profound intellectual disability, generalised seizures, and behavioural disturbances. Our human and mouse data reaffirm IQSEC2 as another disease gene with an unexpected X-chromosome heterozygous female phenotype. Our Iqsec2 mouse model recapitulates the phenotypes observed in human patients despite the differences in the IQSEC2/Iqsec2 gene X-chromosome inactivation between the species.

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“…A challenge in these preclinical drug trials has been the comparison of findings across models, given the different species (rats vs other animal models), different induction protocols, developmental periods of exposure to the drugs, and treatment protocols (pre-vs posttreatments) (150,155,157,161,537,542,545). Hopefully identification of biomarkers guiding treatment implementation would help de-risk the process of selecting promising candidates for transitioning in clinical trials, as well as optimizing treatment protocols and designs.…”

Section: The Search For Personalised Treatment Approachesmentioning

confidence: 99%

Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum

Guerrini

Conti

Mantegazza

et al. 2023

Physiological Reviews

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Developmental and epileptic encephalopathies are a heterogeneous group of disorders characterized by early-onset, often severe epileptic seizures, EEG abnormalities, on a background of developmental impairment that tends to worsen as a consequence of epilepsy. DEEs may result from both non-genetic and genetic etiologies. Genetic DEEs have been associated with mutations in many genes involved in different functions including cell migration, proliferation, and organization, neuronal excitability, and synapse transmission and plasticity. Functional studies performed in different animal models and clinical trials on patients have contributed to elucidate pathophysiological mechanisms underlying many DEEs and explored the efficacy of different treatments. Here, we provide an extensive review of the phenotypic spectrum included in the DEEs, of the genetic determinants and pathophysiological mechanisms underlying these conditions. We also provide a brief overview of the most effective treatment now available and of the emerging therapeutic approaches.

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Extensive phenotyping of two ARX polyalanine expansion mutation mouse models that span clinical spectrum of intellectual disability and epilepsy

Cited by 8 publications

References 54 publications

A new mouse model of ARX dup24 recapitulates the patients’ behavioral and fine motor alterations

A new mouse model of ARX dup24 recapitulates the patients’ behavioral and fine motor alterations

Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females

Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum

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