Genetic variants in TRPM7 associated with unexplained stillbirth modify ion channel function
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
INTRODUCTION: Stillbirth is the loss of a foetus after 22 weeks of gestation, of which almost half go completely unexplained despite post-mortem. We recently sequenced 35 arrhythmia-associated genes from 70 unexplained stillbirth cases. Our hypothesis was that deleterious mutations in channelopathy genes may have a functional effect in utero that may be pro-arrhythmic in the developing foetus. We observed four heterozygous, nonsynonymous variants in TRPM7, a ubiquitously expressed ion channel known to regulate cardiac development and repolarisation in mice. METHODS: We used site-directed mutagenesis and single-cell patch-clamp to analyse the functional effect of the four stillbirth mutants on TRPM7 ion channel function in heterologous cells. We also used cardiomyocytes derived from human pluripotent stem cells to model the contribution of TRPM7 to action potential morphology. RESULTS: Our results show that two TRPM7 variants, p.G179V and p.T860M lead to a marked reduction in ion channel conductance. This observation was underpinned by a lack of measurable TRPM7 protein expression, which in the case of p.T860M was due to rapid proteasomal degradation. We also report that human hiPSC-derived cardiomyocytes possess measurable TRPM7 currents, however siRNA knockdown did not directly affect action potential morphology. CONCLUSION: TRPM7 variants found in the unexplained stillbirth population adversely affect ion channel function and this may precipitate fatal arrhythmia in utero.
Date Issued
2020-06-01
Date Acceptance
2019-08-06
Citation
Human Molecular Genetics, 2020, 29 (11), pp.1797-1807
ISSN
0964-6906
Publisher
Oxford University Press (OUP)
Start Page
1797
End Page
1807
Journal / Book Title
Human Molecular Genetics
Volume
29
Issue
11
Copyright Statement
© The Author(s) 2019. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
License URL
Sponsor
National Institute for Health Research
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/31423533
PII: 5551102
Grant Number
NIHR/CS/010/022
Subjects
Genetics & Heredity
06 Biological Sciences
11 Medical and Health Sciences
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2019-08-19