Journal Article

Potassium Channel KCNH1 Activating Variants Cause Altered Functional and Morphological Ciliogenesis

Lazzari, Sara, Traversa, Alice, Mazza, Tommaso, Tartaglia, Marco, Pace, Valentina, Carella, Massimo, Caputo, Viviana, Petrizzelli, Francesco, Cogoni, Carlo, Giovannetti, Agnese, Catalanotto, Caterina, Pizzuti, Antonio, Parisi, Chiara, Panzironi, Noemi, Napoli, Giulia

2022

Overview

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-à-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.

• Publisher: Springer US,Springer Nature B.V
• Subject: Abnormalities, Multiple / Ataxia / Autism / Autism Spectrum Disorder / Biomedical and Life Sciences / Biomedicine / Cell Biology / Cell cycle / Cell differentiation / Cell proliferation / Cilia / Ciliopathies - genetics / Ciliopathies - pathology / Coronary artery disease / Craniofacial Abnormalities / Cytology / Epilepsy / Epilepsy - genetics / Ether-A-Go-Go Potassium Channels - genetics / Ether-A-Go-Go Potassium Channels - metabolism / Fibroblasts / Fibromatosis, Gingival / Hallux - abnormalities / Hand Deformities, Congenital / Heart diseases / Hedgehog protein / Hedgehog Proteins - metabolism / Humans / Intellectual Disability / Intracellular signalling / Localization / Membrane potential / Mental disorders / Molecular modelling / Morphology / Nails, Malformed / Neurobiology / Neurodevelopmental disorders / Neurology / Neurosciences / Phenotypes / Potassium / Potassium - metabolism / Potassium channels (voltage-gated) / Retina / Schizophrenia / Thumb - abnormalities