Please use this identifier to cite or link to this item: https://www.um.edu.mt/library/oar/handle/123456789/28279
Title: Genetically induced dysfunctions of Kir2.1 channels : implications for short QT3 syndrome and autism-epilepsy phenotype
Authors: Ambrosini, Elena
Sicca, Federico
Brignone, Maria Stefania
D'Adamo, Maria Cristina
Napolitano, Carlo
Servettini, Ilenio
Moro, Francesca
Ruan, Yanfei
Guglielmi, Luca
Pieroni, Stefania
Servillo, Giuseppe
Lanciotti, Angela
Valvo, Giulia
Catacuzzeno, Luigi
Franciolini, Fabio
Molinari, Paola
Marchese, Maria
Grottesi, Alessandro
Guerrini, Renzo
Santorelli, Filippo Maria
Priori, Silvia Giuliana
Pessia, Mauro
Keywords: Potassium channels
Astrocytomas
Autism spectrum disorders
Autism
Epilepsy
Issue Date: 2014
Publisher: Oxford University Press
Citation: Ambrosini, E., Sicca, F., Brignone, M. S., D'adamo, M. C., Napolitano, C., Servettini, I.,...Pessia, M. (2014). Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism-epilepsy phenotype. Human Molecular Genetics, 23(18), 4875-4886.
Abstract: 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.
URI: https://www.um.edu.mt/library/oar//handle/123456789/28279
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