更新于：2024-11-01

Kv12.2 x Potassium channel

更新于：2024-11-01

基本信息

关联

项与 Kv12.2 x Potassium channel 相关的药物

ASP7967

靶点

Kv12.2

作用机制

Kv12.2阻滞剂

在研机构

Astellas Pharma, Inc. [+1]

原研机构

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

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

EM-902

靶点

Kv12.2 x Potassium channel

作用机制

Kv12.2阻滞剂 [+1]

在研机构-

原研机构

Astellas Pharma, Inc.

在研适应症-

非在研适应症

阿尔茨海默症 [+3]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 Kv12.2 x Potassium channel 相关的临床试验

NL-OMON32022 / CompletedN/A

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

开始日期2008-05-04

申办/合作机构

Astellas Pharma, Inc.

100 项与 Kv12.2 x Potassium channel 相关的临床结果

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100 项与 Kv12.2 x Potassium channel 相关的转化医学

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0 项与 Kv12.2 x Potassium channel 相关的专利（医药）

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项与 Kv12.2 x Potassium channel 相关的文献（医药）

2024-11-01·Gene

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

Article

作者: 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.

2023-09-04·The Journal of general physiology

Kv12-encoded K+ channels drive the day-night switch in the repetitive firing rates of SCN neurons.

Article

作者: Nerbonne, Jeanne M ; Hermanstyne, Tracey O ; Mellor, Rebecca L ; Granados-Fuentes, Daniel ; Herzog, Erik D ; Jegla, Timothy ; Li, Xiaofan ; Yang, Nien-Du

Considerable evidence suggests that day-night rhythms in the functional expression of subthreshold potassium (K+) channels regulate daily oscillations in the spontaneous firing rates of neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals. The K+ conductance(s) driving these daily rhythms in the repetitive firing rates of SCN neurons, however, have not been identified. To test the hypothesis that subthreshold Kv12.1/Kv12.2-encoded K+ channels play a role, we obtained current-clamp recordings from SCN neurons in slices prepared from adult mice harboring targeted disruptions in the Kcnh8 (Kv12.1-/-) or Kcnh3 (Kv12.2-/-) locus. We found that mean nighttime repetitive firing rates were higher in Kv12.1-/- and Kv12.2-/- than in wild type (WT), SCN neurons. In marked contrast, mean daytime repetitive firing rates were similar in Kv12.1-/-, Kv12.2-/-, and WT SCN neurons, and the day-night difference in mean repetitive firing rates, a hallmark feature of WT SCN neurons, was eliminated in Kv12.1-/- and Kv12.2-/- SCN neurons. Similar results were obtained with in vivo shRNA-mediated acute knockdown of Kv12.1 or Kv12.2 in adult SCN neurons. Voltage-clamp experiments revealed that Kv12-encoded current densities in WT SCN neurons are higher at night than during the day. In addition, the pharmacological block of Kv12-encoded currents increased the mean repetitive firing rate of nighttime, but not daytime, in WT SCN neurons. Dynamic clamp-mediated subtraction of modeled Kv12-encoded currents also selectively increased the mean repetitive firing rates of nighttime WT SCN neurons. Despite the elimination of the nighttime decrease in the mean repetitive firing rates of SCN neurons, however, locomotor (wheel-running) activity remained rhythmic in Kv12.1-/-, Kv12.2-/-, and Kv12.1-targeted shRNA-expressing, and Kv12.2-targeted shRNA-expressing animals.

2023-07-27·BMC genomics

Diagnostic yield and novel candidate genes for neurodevelopmental disorders by exome sequencing in an unselected cohort with microcephaly.

Article

作者: Tang, Jian ; Zhou, Wei ; Zhang, Aihua ; Wang, Chunli ; Gao, Xiucheng ; Lu, Fen ; Fu, Luhan ; Zhang, Luyan ; Qing, Yan ; Zheng, Bixia ; Shi, Wei ; Zhao, Xiaoke ; Zhang, Yue ; Jia, Zhanjun

OBJECTIVESMicrocephaly is caused by reduced brain volume and most usually associated with a variety of neurodevelopmental disorders (NDDs). To provide an overview of the diagnostic yield of whole exome sequencing (WES) and promote novel candidates in genetically unsolved families, we studied the clinical and genetic landscape of an unselected Chinese cohort of patients with microcephaly.METHODSWe performed WES in an unselected cohort of 103 NDDs patients with microcephaly as one of the features. Full evaluation of potential novel candidate genes was applied in genetically undiagnosed families. Functional validations of selected variants were conducted in cultured cells. To augment the discovery of novel candidates, we queried our genomic sequencing data repository for additional likely disease-causing variants in the identified candidate genes.RESULTSIn 65 families (63.1%), causative sequence variants (SVs) and clinically relevant copy number variants (CNVs) with a pathogenic or likely pathogenic (P/LP) level were identified. By incorporating coverage analysis to WES, a pathogenic or likely pathogenic CNV was detected in 15 families (16/103, 15.5%). In another eight families (8/103, 7.8%), we identified variants in newly reported gene (CCND2) and potential novel neurodevelopmental disorders /microcephaly candidate genes, which involved in cell cycle and division (PWP2, CCND2), CDC42/RAC signaling related actin cytoskeletal organization (DOCK9, RHOF), neurogenesis (ELAVL3, PPP1R9B, KCNH3) and transcription regulation (IRF2BP1). By looking into our data repository of 5066 families with NDDs, we identified additional two cases with variants in DOCK9 and PPP1R9B, respectively.CONCLUSIONOur results expand the morbid genome of monogenic neurodevelopmental disorders and support the adoption of WES as a first-tier test for individuals with microcephaly.