title: Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism-epilepsy phenotype.
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.
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy, elena.ambrosini@iss.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Ambrosini
authors.affiliation: Clinical Neurophysiology Laboratory, Department of Developmental Neuroscience and.
authors.forename: Federico
authors.initials: F
authors.lastname: Sicca
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Brignone
authors.affiliation: Faculty of Medicine, Section of Physiology & Biochemistry, Department of Experimental Medicine.
authors.forename: Maria C
authors.initials: MC
authors.lastname: D'Adamo
authors.affiliation: Molecular Cardiology, IRCCS Salvatore Maugeri Foundation, Pavia, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Napolitano
authors.affiliation: Faculty of Medicine, Section of Physiology & Biochemistry, Department of Experimental Medicine.
authors.forename: Ilenio
authors.initials: I
authors.lastname: Servettini
authors.affiliation: Clinical Neurophysiology Laboratory, Department of Developmental Neuroscience and.
authors.forename: Francesca
authors.initials: F
authors.lastname: Moro
authors.affiliation: Molecular Cardiology, IRCCS Salvatore Maugeri Foundation, Pavia, Italy.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Faculty of Medicine, Section of Physiology & Biochemistry, Department of Experimental Medicine.
authors.forename: Luca
authors.initials: L
authors.lastname: Guglielmi
authors.affiliation: Faculty of Medicine, Department of Experimental Medicine and.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pieroni
authors.affiliation: Faculty of Medicine, Department of Experimental Medicine and.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Servillo
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Lanciotti
authors.affiliation: Clinical Neurophysiology Laboratory, Department of Developmental Neuroscience and.
authors.forename: Giulia
authors.initials: G
authors.lastname: Valvo
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Catacuzzeno
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Franciolini
authors.affiliation: Department of Pharmacology, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Molinari
authors.affiliation: Molecular Medicine Laboratory, IRCCS Stella Maris Foundation, Pisa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Marchese
authors.affiliation: Computational Medicine and Biology Group, CASPUR, Rome, Italy and.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Grottesi
authors.affiliation: Clinical Neurophysiology Laboratory, Department of Developmental Neuroscience and Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Molecular Medicine Laboratory, IRCCS Stella Maris Foundation, Pisa, Italy.
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
authors.affiliation: Molecular Cardiology, IRCCS Salvatore Maugeri Foundation, Pavia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Priori
authors.affiliation: Faculty of Medicine, Section of Physiology & Biochemistry, Department of Experimental Medicine.
authors.forename: Mauro
authors.initials: M
authors.lastname: Pessia
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000473:pathology*; D001254:Astrocytoma / Q000378:metabolism; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D051242:Caveolin 1 / Q000378:metabolism; D051243:Caveolin 2 / Q000378:metabolism; D002460:Cell Line; D002648:Child; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006329:Heart Conduction System / Q000002:abnormalities* / Q000473:pathology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism; D014430:Twins, Monozygotic; D014982:Xenopus laevis / Q000196:embryology
chemical_list: C495544:CAV2 protein, human; D051242:Caveolin 1; D051243:Caveolin 2; C489457:KCNJ2 protein, human; D024661:Potassium Channels, Inwardly Rectifying