Vasilescu, C;
Colpan, M;
Ojala, TH;
Manninen, T;
Mutka, A;
Ylänen, K;
Rahkonen, O;
Poutanen, T;
Martelius, L;
Kumari, R;
et al.
Vasilescu, C; Colpan, M; Ojala, TH; Manninen, T; Mutka, A; Ylänen, K; Rahkonen, O; Poutanen, T; Martelius, L; Kumari, R; Hinterding, H; Brilhante, V; Ojanen, S; Lappalainen, P; Koskenvuo, J; Carroll, CJ; Fowler, VM; Gregorio, CC; Suomalainen, A
(2024)
Recessive TMOD1 mutation causes childhood cardiomyopathy.
Commun Biol, 7 (1).
p. 7.
ISSN 2399-3642
https://doi.org/10.1038/s42003-023-05670-9
SGUL Authors: Carroll, Christopher John
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Abstract
Familial cardiomyopathy in pediatric stages is a poorly understood presentation of heart disease in children that is attributed to pathogenic mutations. Through exome sequencing, we report a homozygous variant in tropomodulin 1 (TMOD1; c.565C>T, p.R189W) in three individuals from two unrelated families with childhood-onset dilated and restrictive cardiomyopathy. To decipher the mechanism of pathogenicity of the R189W mutation in TMOD1, we utilized a wide array of methods, including protein analyses, biochemistry and cultured cardiomyocytes. Structural modeling revealed potential defects in the local folding of TMOD1R189W and its affinity for actin. Cardiomyocytes expressing GFP-TMOD1R189W demonstrated longer thin filaments than GFP-TMOD1wt-expressing cells, resulting in compromised filament length regulation. Furthermore, TMOD1R189W showed weakened activity in capping actin filament pointed ends, providing direct evidence for the variant's effect on actin filament length regulation. Our data indicate that the p.R189W variant in TMOD1 has altered biochemical properties and reveals a unique mechanism for childhood-onset cardiomyopathy.
Item Type: | Article | ||||||||||||
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Additional Information: | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2024 | ||||||||||||
Keywords: | Child, Humans, Actin Cytoskeleton, Actins, Myocytes, Cardiac, Mutation, Cardiomyopathies, Tropomodulin, Myocytes, Cardiac, Humans, Cardiomyopathies, Actins, Mutation, Child, Tropomodulin, Actin Cytoskeleton | ||||||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) | ||||||||||||
Journal or Publication Title: | Commun Biol | ||||||||||||
ISSN: | 2399-3642 | ||||||||||||
Language: | eng | ||||||||||||
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Publisher License: | Creative Commons: Attribution 4.0 | ||||||||||||
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PubMed ID: | 38168645 | ||||||||||||
Web of Science ID: | WOS:001135316700006 | ||||||||||||
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URI: | https://openaccess.sgul.ac.uk/id/eprint/116057 | ||||||||||||
Publisher's version: | https://doi.org/10.1038/s42003-023-05670-9 |
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