Case Report: Loss-of-function TRPM4 mutation p.L91Δ implicated in progressive cardiac conduction defect.
Publisher DOI
PubMed ID
41195386
Abstract
Background
The calcium-activated non-specific cation channel TRPM4 mediates membrane depolarization in many cell types, including cardiomyocytes and Purkinje cells. Rare genetic alterations in the TRPM4 gene can cause familial cases of progressive cardiac conduction defects (PCCDs).Methods And Results
Genetic testing was performed using whole-exome sequencing (WES). Modified human embryonic kidney cells overexpressing either wild-type or the variant p.L91Δ of human TRPM4 were used to investigate the biochemical and functional consequences of this deletion. Western blot and biotinylation experiments revealed a significant reduction in the expression of the mutant channel compared with the wild-type. Functional experiments using the patch-clamp approach demonstrated a significant decrease in TRPM4 current, consistent with the biochemical observations.Conclusion
The new TRPM4 in-frame deletion, p.L91Δ, identified in two unrelated patients with a consistent phenotype, causes a significant decrease in channel expression, leading to its loss of function in the heterologous expression system. These findings further exemplify the role of TRPM4 in genetic cardiac channelopathies.
The calcium-activated non-specific cation channel TRPM4 mediates membrane depolarization in many cell types, including cardiomyocytes and Purkinje cells. Rare genetic alterations in the TRPM4 gene can cause familial cases of progressive cardiac conduction defects (PCCDs).Methods And Results
Genetic testing was performed using whole-exome sequencing (WES). Modified human embryonic kidney cells overexpressing either wild-type or the variant p.L91Δ of human TRPM4 were used to investigate the biochemical and functional consequences of this deletion. Western blot and biotinylation experiments revealed a significant reduction in the expression of the mutant channel compared with the wild-type. Functional experiments using the patch-clamp approach demonstrated a significant decrease in TRPM4 current, consistent with the biochemical observations.Conclusion
The new TRPM4 in-frame deletion, p.L91Δ, identified in two unrelated patients with a consistent phenotype, causes a significant decrease in channel expression, leading to its loss of function in the heterologous expression system. These findings further exemplify the role of TRPM4 in genetic cardiac channelopathies.
Date Issued
2025
Publication Type
Article
Subjects
TRPM4
•
calcium-activated non-specific cation channel
•
cardiac conduction defects
•
inherited channelopathy
•
loss-of-function mutation
Language(s)
en
Author(s)
Ross-Kaschitza, Daniela | |
Shestak, Anna | |
Jyh-Ming Juang, Jimmy | |
Ricciardi, Bianca Sol Soloaga | |
Bokhobza, Alexandre François Edmond | |
Zaklyazminskaya, Elena V | |
Gajek, Jacek | |
Hasdemir, Can |
Journal
Frontiers in Physiology
Publisher
Frontiers Media
ISSN
1664-042X
Access(Rights)
open.access