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Last update 08 May 2025

Kv12.2

Last update 08 May 2025

Basic Info

Synonyms

BEC1, Brain-specific eag-like channel 1, ELK channel 2

+ [8]

Introduction

Pore-forming (alpha) subunit of a voltage-gated inwardly rectifying potassium channel (PubMed:10455180). Charactherized by a fast rate of activation during depolarization followed by a rapid inactivation at much more depolarized value causing inward rectification due to a C-type inactivation mechanism (PubMed:10455180). Exhibits a rapid recovery from inactivation (PubMed:10455180).

Drugs associated with Kv12.2

ASP7967

Target

Kv12.2

Mechanism

Kv12.2 blockers

Active Org.

Astellas Pharma, Inc. [+1]

Originator Org.

Okinawa Institute of Science & Technology Promotion Corp. [+1]

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

EM-902

Target

Kv12.2 x Potassium channel

Mechanism

Kv12.2 blockers [+1]

Active Org.-

Originator Org.

Astellas Pharma, Inc.

Active Indication-

Inactive Indication

Alzheimer Disease [+3]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with Kv12.2

NL-OMON32022

/ CompletedNot Applicable

A double-blind, randomized, placebo-controlled study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of single ascending oral doses of ASP2905 in healthy young males, including an open-label two-period randomized crossover study to compare the pharmacokinetics under fasted and fed conditions - ASP2905 SAD/food effect study

Start Date04 May 2008

Sponsor / Collaborator

Astellas Pharma, Inc.

100 Clinical Results associated with Kv12.2

100 Translational Medicine associated with Kv12.2

0 Patents (Medical) associated with Kv12.2

Literatures (Medical) associated with Kv12.2

01 Jul 2025·Seizure: European Journal of Epilepsy

Loss-of-function variant in KCNH3 is associated with global developmental delay, autistic behavior, insomnia, and nocturnal seizures

Article

Author: Bähring, Robert ; Harms, Frederike L ; Grinstein, Lev ; Kortüm, Fanny ; Bauer, Christiane K ; Alawi, Malik ; Denecke, Jonas ; Möllring, Anna

INTRODUCTIONThe KCNH gene family encodes voltage-gated potassium (Kv) channels of the EAG subtype covering three subfamilies (Kv10-12). EAG channels are involved in the control of cardiac and neuronal excitation, and pathogenic variants in KCNH genes encoding Kv10 (eag) and Kv11 (erg) subfamily members cause a broad clinical spectrum ranging from cardiac arrhythmia to neurodevelopmental syndromes. However, no pathogenic variants have been hitherto reported for KCNH genes encoding Kv12 (elk) subfamily members.METHODSClinical, genomic, and functional studies were performed, including voltage-clamp experiments using heterologous channel expression in Xenopus oocytes.RESULTSWe examined an eight-year-old girl presenting with global developmental delay, intellectual disability, autistic and aggressive behavior, hyperactivity, insomnia, and nocturnal seizures. Focal seizures were successfully treated with sulthiame, which reduced the occurrence of temporo-parietal spike-wave paroxysms. Trio exome sequencing revealed a heterozygous de novo missense variant, NM_012284.3:c.1112C>T; p.(Ala371Val), in KCNH3, which encodes the Kv channel α-subunit Kv12.2. The amino acid substitution associated with the KCNH3 variant identified in the patient is located at a site highly conserved in EAG channels. The analogous variant in KCNH2 causes long-QT-syndrome 2, and has also been associated with epilepsy. Electrophysiological characterization of the KCNH3 p.(Ala371Val) variant demonstrated loss-of-function of the mutant Kv12.2 channels and strongly reduced current amplitudes upon co-expression of wildtype and mutant channel subunits in a dominant-negative manner.CONCLUSIONOur results propose KCNH3, which is primarily expressed in the nervous system, as a new disease gene associated with a neurodevelopmental phenotype including seizures.

01 Nov 2024·Gene

Analysis of genes differentially expressed in the cortex of mice with the Tbl1xr1 variant

Article

Author: Falize, Kim ; Boelen, Anita ; Bruinstroop, Eveline ; van Trotsenburg, Paul ; Hu, Yalan ; Hennekam, Raoul C ; Fliers, Eric ; Lauffer, Peter ; Jongejan, Aldo

Transducin β-like 1 X-linked receptor 1 (mouse Tbl1xr1) or TBL1X/Y related 1 (human TBL1XR1), part of the NCoR/SMRT corepressor complex, is involved in nuclear receptor signaling. Variants in TBL1XR1 cause a variety of neurodevelopmental disorders including Pierpont syndrome caused by the p.Tyr446Cys variant. We recently reported a mouse model carrying the Tbl1xr1^Y446C/Y446C variant as a model for Pierpont syndrome. To obtain insight into mechanisms involved in altered brain development we studied gene expression patterns in the cortex of mutant and wild type (WT) mice, using RNA-sequencing, differentially expressed gene (DEG) analysis, gene set enrichment analysis (GSEA), weighted gene correlation network analysis (WGCNA) and hub gene analysis. We validated results in mutated mouse cortex, as well as in BV2 and SK-N-AS cell lines, in both of which Tbl1xr1 was knocked down by siRNA. Two DEGs (adj.P. Val < 0.05) were found in the cortex, Mpeg1 (downregulated in mutant mice) and 2900052N01Rik (upregulated in mutant mice). GSEA, WGCNA and hub gene analysis demonstrated changes in genes involved in ion channel function and neuroinflammation in the cortex of the Tbl1xr1^Y446C/Y446C mice. The lowered expression of ion channel genes Kcnh3 and Kcnj4 mRNA was validated in the mutant mouse cortex, and increased expression of TRIM9, associated with neuroinflammation, was confirmed in the SK-N-AS cell line. Conclusively, our results show altered expression of genes involved in ion channel function and neuroinflammation in the cortex of the Tbl1xr1^Y446C/Y446C mice. These may partly explain the impaired neurodevelopment observed in individuals with Pierpont syndrome and related TBL1XR1-related disorders.

15 Jul 2024·International Journal of Cancer

Exploring the tumor genomic landscape of aggressive prostate cancer by whole‐genome sequencing of tissue or liquid biopsies

Article

Author: Kassentoft, Christine Gaasdal ; Farajzadeh, Leila ; Borre, Michael ; Sørensen, Karina Dalsgaard ; Rusan, Maria ; Nørgaard, Maibritt ; Pedersen, Jakob Skou ; Weiss, Simone ; Ulhøi, Benedicte Parm ; Lamy, Philippe ; Jensen, Jørgen Bjerggaard ; Knudsen, Michael

AbstractTreatment resistance remains a major issue in aggressive prostate cancer (PC), and novel genomic biomarkers may guide better treatment selection. Circulating tumor DNA (ctDNA) can provide minimally invasive information about tumor genomes, but the genomic landscape of aggressive PC based on whole‐genome sequencing (WGS) of ctDNA remains incompletely characterized. Thus, we here performed WGS of tumor tissue (n = 31) or plasma ctDNA (n = 10) from a total of 41 aggressive PC patients, including 11 hormone‐naïve, 15 hormone‐sensitive, and 15 castration‐resistant patients. Across all variant types, we found progressively more altered tumor genomic profiles in later stages of aggressive PC. The potential driver genes most frequently affected by single‐nucleotide variants or insertions/deletions included the known PC‐related genes TP53, CDK12, and PTEN and the novel genes COL13A1, KCNH3, and SENP3. Etiologically, aggressive PC was associated with age‐related and DNA repair‐related mutational signatures. Copy number variants most frequently affected 14q11.2 and 8p21.2, where no well‐recognized PC‐related genes are located, and also frequently affected regions near the known PC‐related genes MYC, AR, TP53, PTEN, and BRCA1. Structural variants most frequently involved not only the known PC‐related genes TMPRSS2 and ERG but also the less extensively studied gene in this context, PTPRD. Finally, clinically actionable variants were detected throughout all stages of aggressive PC and in both plasma and tissue samples, emphasizing the potential clinical applicability of WGS of minimally invasive plasma samples. Overall, our study highlights the feasibility of using liquid biopsies for comprehensive genomic characterization as an alternative to tissue biopsies in advanced/aggressive PC.

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Kv12.2

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