Recessive TMOD1 mutation causes childhood cardiomyopathy
| Author(s) | Vasilescu, Catalina | |
| Author(s) | Colpan, Mert | |
| Author(s) | Ojala, Tiina H. | |
| Author(s) | Manninen, Tuula | |
| Author(s) | Mutka, Aino | |
| Author(s) | Ylänen, Kaisa | |
| Author(s) | Rahkonen, Otto | |
| Author(s) | Poutanen, Tuija | |
| Author(s) | Martelius, Laura | |
| Author(s) | Kumari, Reena | |
| Author(s) | Hinterding, Helena | |
| Author(s) | Brilhante, Virginia | |
| Author(s) | Ojanen, Simo | |
| Author(s) | Lappalainen, Pekka | |
| Author(s) | Koskenvuo, Juha | |
| Author(s) | Carroll, Christopher J. | |
| Author(s) | Fowler, Velia M. | |
| Author(s) | Gregorio, Carol C. | |
| Author(s) | Suomalainen, Anu | |
| Date Accessioned | 2024-03-01T18:28:16Z | |
| Date Available | 2024-03-01T18:28:16Z | |
| Publication Date | 2024-01-02 | |
| Description | This article was originally published in Communications Biology. The version of record is available at: https://doi.org/10.1038/s42003-023-05670-9. © The Author(s) 2024. This article was featured in a UDaily article on 2/29/2024 at: https://www.udel.edu/udaily/2024/february/red-blood-cell-research-velia-fowler/ | |
| 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. | |
| Sponsor | The authors thank Markus Innilä and Rachel Mayfield for technical support. Biomedicum Imaging Unit facility is acknowledged for providing infrastructure and services. CSC-IT Center for Science Finland is acknowledged for computational resources. The funding was provided by the Finnish Foundation for Cardiovascular Research, Jane and Aatos Erkko Foundation, Sigrid Jusélius Foundation, Academy of Finland, University of Helsinki, Finnish Cultural Foundation, Alfred Kordelin Foundation, Otto Malm Foundation, Maud Kuistila Foundation, Foundation for Pediatric Research Finland, National Institutes of Health (R01HL123078, R01HL164644), American Heart Association (19POST34450023) and Czarina M. and Humberto S. Lopez Endowed Chair for Excellence in Cardiovascular Research. | |
| Citation | Vasilescu, C., Colpan, M., Ojala, T.H. et al. Recessive TMOD1 mutation causes childhood cardiomyopathy. Commun Biol 7, 7 (2024). https://doi.org/10.1038/s42003-023-05670-9 | |
| ISSN | 2399-3642 | |
| URL | https://udspace.udel.edu/handle/19716/34088 | |
| Language | en_US | |
| Publisher | Communications Biology | |
| dc.rights | Attribution 4.0 International | en |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
| Keywords | actin | |
| Keywords | cardiomyopathies | |
| Keywords | cardiovascular genetics | |
| Title | Recessive TMOD1 mutation causes childhood cardiomyopathy | |
| Type | Article |
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