Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 32 min ago
PreprintCC BYbioRxiv

Functional Screening of Kv7.5 Channel Variants Associated with Neuronal Dysfunction

  • D. V. Hunter
  • S. Vishwakarma
  • N. Givzad
  • J. Liu
  • M. Sanei
  • B. Kersey
  • R. I. Klein Geltink
  • D. T. Poburko
  • M. Prondzynski
  • T. Claydon1
  1. 1Simon Fraser University
Read full textPDFDOICite

Abstract

The KCNQ5 gene encodes Kv7.5 channels, which contribute to the regulation of neuronal excitability. Kv7.5 genetic variants associated with neurological dysfunction have been reported, but functional characterization of Kv7.5 variants is limited and causal links to pathogenicity are lacking. We have conducted the first automated patch clamp functional screen of a panel of heterozygous Kv7.5/Kv7.3 channel variants. We tested nine mutations located in diverse locations throughout the Kv7.5 channel and identified some variants with gain-of-function effects (L341I+/-, G347S+/-, P369R+/-, R497C+/-), some with loss-of-function effects (V145G+/-, W303C+/-), and others with no apparent effect (A131V+/-, R359H+/-, R491H+/-). Variants produced a gain of function by left-shifting the voltage-dependence of channel activation alone or in combination with increasing current density. Loss of function occurred as a result of reduced current density. Using these findings, we initiated the first z-score classification to guide understanding of Kv7.5 variant pathogenicity, which can be refined as more variants are functionally characterized and new variants are discovered. Lastly, we observed higher sensitivity to channel block by XE991 in L341I+/-, G347S+/-, P369R+/- gain-of-function variants indicating potential for targeted pharmacogenetic approaches to restore normal Kv7.5 channel function.

Related

  1. Functional assessment of CELSR1 variants associated with human developmental defects.
    Jazmin M Stenson, William Giang, Sarah G Latario +4
    Frontiers in cell and developmental biologyPeer-reviewedCC BYFull textMolecular biology & gene regulationEurope PMC
  2. De novo structural variants in autism spectrum disorder disrupt distal regulatory interactions of neuronal genes
    Ketrin Gjoni, Xingjie Ren, Amanda Everitt +2
    Genome ResearchPreprintLicence not stated7 citedMolecular biology & gene regulationOpenAlex
  3. Emerging extranuclear roles of protein SUMOylation in neuronal function and dysfunction
    Stéphane Martin, Kevin Wilkinson, Atsushi Nishimune +1
    Nature Reviews NeurosciencePeer-reviewedLicence not stated207 citedMolecular biology & gene regulationHAL
  4. Rapid Screening of Early SARS-CoV-2 Variants of Concern by Pyrosequencing
    Susanne C. Duwe, Ashkan Ghassemi, Sofia Paraskevopoulou +6
    International Journal of Molecular SciencesPeer-reviewedCC BY 4.0General biochemistryCrossref
  5. Functional impact of PCSK9 variants on LDL uptake in a knockout hepatic model
    Hongmei Li, Huili Liu, Wenxin Xu +7
    PLOS OnePeer-reviewedCC BY 4.0Full textMolecular biology & gene regulationPLOS

Cite

BibTeXRIS
BibTeX
@misc{hunter2026functional,
  title = {{Functional Screening of Kv7.5 Channel Variants Associated with Neuronal Dysfunction}},
  author = {D. V. Hunter and S. Vishwakarma and N. Givzad and J. Liu and M. Sanei and B. Kersey and R. I. Klein Geltink and D. T. Poburko and M. Prondzynski and T. Claydon},
  howpublished = {bioRxiv},
  year = {2026},
  month = nov,
  doi = {10.64898/2026.11.02.763732},
  url = {https://www.biorxiv.org/content/10.64898/2026.11.02.763732v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Functional Screening of Kv7.5 Channel Variants Associated with Neuronal Dysfunction
AU  - D. V. Hunter
AU  - S. Vishwakarma
AU  - N. Givzad
AU  - J. Liu
AU  - M. Sanei
AU  - B. Kersey
AU  - R. I. Klein Geltink
AU  - D. T. Poburko
AU  - M. Prondzynski
AU  - T. Claydon
PY  - 2026
DA  - 2026/11/02
PB  - bioRxiv
DO  - 10.64898/2026.11.02.763732
UR  - https://www.biorxiv.org/content/10.64898/2026.11.02.763732v1
AB  - The KCNQ5 gene encodes Kv7.5 channels, which contribute to the regulation of neuronal excitability. Kv7.5 genetic variants associated with neurological dysfunction have been reported, but functional characterization of Kv7.5 variants is limited and causal links to pathogenicity are lacking. We have conducted the first automated patch clamp functional screen of a panel of heterozygous Kv7.5/Kv7.3 channel variants. We tested nine mutations located in diverse locations throughout the Kv7.5 channel and identified some variants with gain-of-function effects (L341I+/-, G347S+/-, P369R+/-, R497C+/-), some with loss-of-function effects (V145G+/-, W303C+/-), and others with no apparent effect (A131V+/-, R359H+/-, R491H+/-). Variants produced a gain of function by left-shifting the voltage-dependence of channel activation alone or in combination with increasing current density. Loss of function occurred as a result of reduced current density. Using these findings, we initiated the first z-score classification to guide understanding of Kv7.5 variant pathogenicity, which can be refined as more variants are functionally characterized and new variants are discovered. Lastly, we observed higher sensitivity to channel block by XE991 in L341I+/-, G347S+/-, P369R+/- gain-of-function variants indicating potential for targeted pharmacogenetic approaches to restore normal Kv7.5 channel function.
ER  -