Lauritano, Anna (2019) Exploring the role of Kv7.3 in excitability control: novel insights from human mutations and a mice model. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Lingua: English
Title: Exploring the role of Kv7.3 in excitability control: novel insights from human mutations and a mice model
Date: 11 December 2019
Number of Pages: 137
Institution: Università degli Studi di Napoli Federico II
Department: Neuroscienze e Scienze Riproduttive ed Odontostomatologiche
Dottorato: Neuroscienze
Ciclo di dottorato: 32
Coordinatore del Corso di dottorato:
Taglialatela, MaurizioUNSPECIFIED
Taglialatela, MaurizioUNSPECIFIED
Date: 11 December 2019
Number of Pages: 137
Uncontrolled Keywords: Kv7.3; M-current; neuronal excitability; LoF; Gof; epilepsy; ID; autism
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/14 - Farmacologia
Area 05 - Scienze biologiche > BIO/18 - Genetica
Area 06 - Scienze mediche > MED/26 - Neurologia
Date Deposited: 07 Jan 2020 10:59
Last Modified: 17 Nov 2021 12:09


The KCNQ3 gene encodes for voltage-gated potassium channel subunits known as Kv7.3 which, together with subunits encoded by other members of the KCNQ gene subfamily, provide a critical contribution to the M-current. This current is a major controller of neuronal excitability at distinct brain areas and neuronal subtypes, as also revealed by the fact that variants in Kv7.3 cause mostly neonatal-onset epilepsies with wide phenotypic heterogeneity. However, despite these genetic evidences, several questions regarding the role of Kv7.3 subunits in controlling the excitability of specific brain regions and neuronal subtypes as well as the molecular pathophysiology of the human phenotypes associated to Kv7.3 variants are still poorly understood. In the present study, I have addressed some of these pressing issues in KCNQ3 neurobiology using tools and models ranging from kcnq3 KO mice to individuals/families carrying Kv7.3 mutations. In particular, using electrophysiological recordings in brain slices from kcnq3 KO mice, I have evaluated the role of Kv7.3 channel subunits in controlling the excitability of neurons located in the subiculum, the main output of the hippocampal circuit, and in the hippocampal CA1 area; notably, both the subuculum and the hippocampal formation are two cortical brain regions critically involved in seizure onset and propagation. In addition, I reported the functional consequences of mutations in Kv7.3 found associated with distinct clinical phenotypes in humans. In particular, I have investigated ex vivo and in vitro consequences of a new Kv7.3 variant (Kv7.3 F534Ifs*15), found in homozygous configuration in a 9‐year‐old girl with pharmacodependent neonatal‐onset epilepsy and non‐syndromic intellectual disability. This specific variant represents a unique opportunity to investigate the consequence of a complete deletion of Kv7.3 in humans given that all previously-found Kv7.3 mutations, except one, are found in heterozygosity. Finally, I have carried out electrophysiological and modeling studies to evaluated the functional consequences on channel properties determined by four de novo variants (Kv7.3-R227Q, -R230C, -R230S, and -R230C) found in patients with global neurodevelopmental disability (NDD), autism spectrum disorder (ASD), and Sleep-Activated Near-Continuous Multifocal Spikes. These pathogenic variants have been of great relevance given that were responsible of a unique phenotype, not associated to neonatal-onset seizure, which allowed a further expansion of the phenotypic spectrum of diseases associated to Kv7.3 gene variants.


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