Autism with Seizures and Intellectual Disability: Possible Causative Role of Gain-of-function of the Inwardly-Rectifying K+ Channel Kir4.1

Sicca, Federico; Imbrici, Paola; D’Adamo, Maria Cristina; Moro, Francesca; Bonatti, Fabrizia; Brovedani, Paola; Grottesi, Alessandro; Guerrini, Renzo; Masi, Gabriele; Santorelli, Filippo M.; Pessia, Mauro

doi:10.1016/j.nbd.2011.03.016

Cited by 102 publications

(112 citation statements)

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“…The clinical case of the two probands has been reported both as SI data and elsewhere (11). In brief, two 9-year-old identical twins (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…Kir2.1 channels are highly expressed in the brain, particularly in hippocampus, caudate, putamen, nucleus accumbens, habenula and amygdala (41), all areas implicated in cognition, mood disorders and ASD. As Kir2 channels, together with Kir4.1 and Kir5.1, contribute to regulate neuronal excitability, cell differentiation, synaptic plasticity and wiring, their dysfunction may impact these crucial neurophysiological processes and result in functional impairment of neural networks (further discussed in 11,12; 42–44). The clinical findings and mechanistic insights provided here, combined with recent studies showing the presence of neuropsychiatric disorders in individuals with mutations in KCNJ2 (2,4–6), indicate a possible role of the Kir2.1 channels in the pathogenesis of autism–epilepsy.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, whether Kir2.1 channels function as anti-convulsant or proconvulsant is unclear. Intriguingly, in both twins seizures had a short course and EEGs normalized by the age of 3 years (11). …”

Section: Discussionmentioning

confidence: 99%

“…Those findings highlighted an emerging role for the inwardly rectifying K + channels dysfunction in autism–epilepsy associated with intellectual disability, which warranted further investigations (11,12). We herein report on the identification of a new p.K346T mutation in KCNJ2 in cis with the previously detected p.R18Q variant in KCNJ10 (11). The pathogenic relevance of the mutation was assessed in Xenopus laevis oocytes, HEK293 and glial-like cells.…”

Section: Introductionmentioning

confidence: 97%

“…We recently reported on two homozygous twins manifesting intellectual disability, autism spectrum disorder (ASD), and a history of infantile spasms where we detected gain-of-function mutations in KCNJ10 , encoding the Kir4.1 channel (11). Those findings highlighted an emerging role for the inwardly rectifying K + channels dysfunction in autism–epilepsy associated with intellectual disability, which warranted further investigations (11,12).…”

Section: Introductionmentioning

confidence: 99%

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Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism–epilepsy phenotype

Ambrosini

Sicca

Brignone

et al. 2014

Human Molecular Genetics

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Short QT3 syndrome (SQT3S) is a cardiac disorder characterized by a high risk of mortality and associated with mutations in Kir2.1 (KCNJ2) channels. The molecular mechanisms leading to channel dysfunction, cardiac rhythm disturbances and neurodevelopmental disorders, potentially associated with SQT3S, remain incompletely understood. Here, we report on monozygotic twins displaying a short QT interval on electrocardiogram recordings and autism–epilepsy phenotype. Genetic screening identified a novel KCNJ2 variant in Kir2.1 that (i) enhanced the channel's surface expression and stability at the plasma membrane, (ii) reduced protein ubiquitylation and degradation, (iii) altered protein compartmentalization in lipid rafts by targeting more channels to cholesterol-poor domains and (iv) reduced interactions with caveolin 2. Importantly, our study reveals novel physiological mechanisms concerning wild-type Kir2.1 channel processing by the cell, such as binding to both caveolin 1 and 2, protein degradation through the ubiquitin–proteasome pathway; in addition, it uncovers a potential multifunctional site that controls Kir2.1 surface expression, protein half-life and partitioning to lipid rafts. The reported mechanisms emerge as crucial also for proper astrocyte function, suggesting the need for a neuropsychiatric evaluation in patients with SQT3S and offering new opportunities for disease management.

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“…The clinical case of the two probands has been reported both as SI data and elsewhere (11). In brief, two 9-year-old identical twins (Fig.…”

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism–epilepsy phenotype

Ambrosini

Sicca

Brignone

et al. 2014

Human Molecular Genetics

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Genetic modifications associated with ketogenic diet treatment in the BTBR^T+Tf/J mouse model of autism spectrum disorder

Mychasiuk

Rho

2016

Autism Research

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Although our study supports many of the previously known impairments associated with ASD, such as excessive myelin formation and impaired GABAergic transmission, the RNAseq data and pathway analysis utilized here identified new therapeutic targets for analysis, such as Vitamin D pathways and cAMP signaling. Autism Res 2017, 10: 456-471. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

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Astrocyte dysfunction in temporal lobe epilepsy: K⁺ channels and gap junction coupling

Steinhäuser

Seifert

Bedner

2012

Glia

169

172

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Astrocytes are endowed with the machinery to sense and respond to neuronal activity. Recent work has demonstrated that astrocytes play important physiological roles in the CNS, e.g., they synchronize action potential firing, ensure ion homeostasis, transmitter clearance and glucose metabolism, and regulate the vascular tone. Astrocytes are abundantly coupled through gap junctions, which is a prerequisite to redistribute elevated K 1 from sites of excessive neuronal activity to sites of lower extracellular K 1 concentration. Recent studies identified dysfunctional astrocytes as crucial players in epilepsy. Investigation of specimens from patients with pharmacoresistant temporal lobe epilepsy and epilepsy models revealed alterations in expression, localization, and function of astroglial inwardly rectifying K 1 (Kir) channels, particularly Kir4.1, which is suspected to entail impaired K 1 buffering. Gap junctions in astrocytes appear to play a dual role: on the one hand they counteract the generation of hyperactivity by facilitating clearance of elevated extracellular K 1 levels while in contrast, they constitute a pathway for energetic substrate delivery to fuel neuronal (hyper)activity. Recent work suggests that astrocyte dysfunction is causative of the generation or spread of seizure activity. Thus, astrocytes should be considered as promising targets for alternative antiepileptic therapies. V V C 2012 Wiley Periodicals, Inc.

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Autism with Seizures and Intellectual Disability: Possible Causative Role of Gain-of-function of the Inwardly-Rectifying K+ Channel Kir4.1

Cited by 102 publications

References 74 publications

Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism–epilepsy phenotype

Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism–epilepsy phenotype

Genetic modifications associated with ketogenic diet treatment in the BTBR^T+Tf/J mouse model of autism spectrum disorder

Astrocyte dysfunction in temporal lobe epilepsy: K⁺ channels and gap junction coupling

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Autism with Seizures and Intellectual Disability: Possible Causative Role of Gain-of-function of the Inwardly-Rectifying K+ Channel Kir4.1

Cited by 102 publications

References 74 publications

Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism–epilepsy phenotype

Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism–epilepsy phenotype

Genetic modifications associated with ketogenic diet treatment in the BTBRT+Tf/J mouse model of autism spectrum disorder

Astrocyte dysfunction in temporal lobe epilepsy: K+ channels and gap junction coupling

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Product

Resources

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Genetic modifications associated with ketogenic diet treatment in the BTBR^T+Tf/J mouse model of autism spectrum disorder

Astrocyte dysfunction in temporal lobe epilepsy: K⁺ channels and gap junction coupling