Related Experiment Video
Updated: Jan 20, 2026
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Mutagenesis and Functional Analysis of Ion Channels Heterologously Expressed in Mammalian Cells
Published on: October 1, 2010
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Genetic variants in TRPM7 associated with unexplained stillbirth modify ion channel function
James H Cartwright1, Qadeer Aziz1, Stephen C Harmer1,2
1Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
Human Molecular Genetics
|August 20, 2019
Summary
Deleterious mutations in the TRPM7 ion channel may cause unexplained stillbirth. Variants identified in stillbirth cases significantly reduce TRPM7 channel function, potentially leading to fatal fetal arrhythmias in utero.
Area of Science:
- Genetics
- Cardiology
- Developmental Biology
Background:
- Stillbirth affects nearly half of fetuses, often with unexplained causes despite post-mortem examinations.
- Genetic mutations in ion channels are hypothesized to contribute to unexplained fetal loss.
Purpose of the Study:
- To investigate the role of deleterious mutations in arrhythmia-associated genes, specifically TRPM7, in unexplained stillbirth.
- To functionally characterize identified TRPM7 variants in vitro and in human-derived cardiomyocytes.
Main Methods:
- Sequencing of 35 arrhythmia-associated genes in 70 unexplained stillbirth cases.
- Site-directed mutagenesis and single-cell patch-clamp electrophysiology to analyze TRPM7 variants.
- Utilizing human induced pluripotent stem cell-derived cardiomyocytes to model TRPM7 function.
Main Results:
- Four heterozygous, nonsynonymous TRPM7 variants were identified in unexplained stillbirth cases.
- Two variants (p.G179V and p.T860M) significantly reduced TRPM7 ion channel conductance, with p.T860M showing impaired protein expression due to proteasomal degradation.
- TRPM7 currents were measurable in human cardiomyocytes, but siRNA knockdown did not directly alter action potential morphology.
Conclusions:
- TRPM7 variants found in unexplained stillbirth cases impair ion channel function.
- These functional deficits may precipitate fatal arrhythmias during fetal development, contributing to stillbirth.
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