The primary cilium is a non-motile sensory organelle that extends from the surface of most vertebrate cells and transduces signals regulating proliferation, differentiation, and migration. Primary cilia dysfunctions have been observed in cancer and in a group of heterogeneous disorders called ciliopathies, characterized by renal and liver cysts, skeleton and limb abnormalities, retinal degeneration, intellectual disability, ataxia, and heart disease and, recently, in autism spectrum disorder, schizophrenia, and epilepsy. The potassium voltage-gated channel subfamily H member 1 (KCNH1) gene encodes a member of the EAG (ether-a-go-go) family, which controls potassium flux regulating resting membrane potential in both excitable and non-excitable cells and is involved in intracellular signaling, cell proliferation, and tumorigenesis. KCNH1 missense variants have been associated with syndromic neurodevelopmental disorders, including Zimmermann-Laband syndrome 1 (ZLS1, MIM #135500), Temple-Baraitser syndrome (TMBTS, MIM #611816), and, recently, with milder phenotypes as epilepsy. In this work, we provide evidence that KCNH1 localizes at the base of the cilium in pre-ciliary vesicles and ciliary pocket of human dermal fibroblasts and retinal pigment epithelial (hTERT RPE1) cells and that the pathogenic missense variants (L352V and R330Q; NP_002229.1) perturb cilia morphology, assembly/disassembly, and Sonic Hedgehog signaling, disclosing a multifaceted role of the protein. The study of KCNH1 localization, its functions related to primary cilia, and the alterations introduced by mutations in ciliogenesis, cell cycle coordination, cilium morphology, and cilia signaling pathways could help elucidate the molecular mechanisms underlying neurological phenotypes and neurodevelopmental disorders not considered as classical ciliopathies but for which a significant role of primary cilia is emerging.

Potassium Channel {KCNH}1 Activating Variants Cause Altered Functional and Morphological Ciliogenesis / Napoli, Giulia; Panzironi, Noemi; Traversa, Alice; Catalanotto, Caterina; Pace, Valentina; Petrizzelli, Francesco; Giovannetti, Agnese; Lazzari, Sara; Cogoni, Carlo; Tartaglia, Marco; Carella, Massimo; Mazza, Tommaso; Pizzuti, Antonio; Parisi, Chiara; Caputo, Viviana. - In: MOLECULAR NEUROBIOLOGY. - ISSN 0893-7648. - (2022). [10.1007/s12035-022-02886-4]

Potassium Channel {KCNH}1 Activating Variants Cause Altered Functional and Morphological Ciliogenesis

Alice Traversa;Caterina Catalanotto;Francesco Petrizzelli;Sara Lazzari;Carlo Cogoni;Antonio Pizzuti;Chiara Parisi
Penultimo
;
Viviana Caputo
Ultimo
2022

Abstract

The primary cilium is a non-motile sensory organelle that extends from the surface of most vertebrate cells and transduces signals regulating proliferation, differentiation, and migration. Primary cilia dysfunctions have been observed in cancer and in a group of heterogeneous disorders called ciliopathies, characterized by renal and liver cysts, skeleton and limb abnormalities, retinal degeneration, intellectual disability, ataxia, and heart disease and, recently, in autism spectrum disorder, schizophrenia, and epilepsy. The potassium voltage-gated channel subfamily H member 1 (KCNH1) gene encodes a member of the EAG (ether-a-go-go) family, which controls potassium flux regulating resting membrane potential in both excitable and non-excitable cells and is involved in intracellular signaling, cell proliferation, and tumorigenesis. KCNH1 missense variants have been associated with syndromic neurodevelopmental disorders, including Zimmermann-Laband syndrome 1 (ZLS1, MIM #135500), Temple-Baraitser syndrome (TMBTS, MIM #611816), and, recently, with milder phenotypes as epilepsy. In this work, we provide evidence that KCNH1 localizes at the base of the cilium in pre-ciliary vesicles and ciliary pocket of human dermal fibroblasts and retinal pigment epithelial (hTERT RPE1) cells and that the pathogenic missense variants (L352V and R330Q; NP_002229.1) perturb cilia morphology, assembly/disassembly, and Sonic Hedgehog signaling, disclosing a multifaceted role of the protein. The study of KCNH1 localization, its functions related to primary cilia, and the alterations introduced by mutations in ciliogenesis, cell cycle coordination, cilium morphology, and cilia signaling pathways could help elucidate the molecular mechanisms underlying neurological phenotypes and neurodevelopmental disorders not considered as classical ciliopathies but for which a significant role of primary cilia is emerging.
2022
Epilepsy; KCNH1; Neurodevelopmental disorder; Potassium channel; Primary cilium; SHH pathway
01 Pubblicazione su rivista::01a Articolo in rivista
Potassium Channel {KCNH}1 Activating Variants Cause Altered Functional and Morphological Ciliogenesis / Napoli, Giulia; Panzironi, Noemi; Traversa, Alice; Catalanotto, Caterina; Pace, Valentina; Petrizzelli, Francesco; Giovannetti, Agnese; Lazzari, Sara; Cogoni, Carlo; Tartaglia, Marco; Carella, Massimo; Mazza, Tommaso; Pizzuti, Antonio; Parisi, Chiara; Caputo, Viviana. - In: MOLECULAR NEUROBIOLOGY. - ISSN 0893-7648. - (2022). [10.1007/s12035-022-02886-4]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1648078
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