Recessive TMOD1 mutation causes childhood cardiomyopathy

Catalina Vasilescu; Mert Colpan; Tiina H. Ojala; Tuula Manninen; Aino Mutka; Kaisa Ylänen; Otto Rahkonen; Tuija Poutanen; Laura Martelius; Reena Kumari; Helena Hinterding; Virginia Brilhante; Simo Ojanen; Pekka Lappalainen; Juha Koskenvuo; Christopher J. Carroll; Velia M. Fowler; Carol C. Gregorio; Anu Suomalainen

doi:10.1038/s42003-023-05670-9

Recessive TMOD1 mutation causes childhood cardiomyopathy

Catalina Vasilescu
, Mert Colpan
, Tiina H. Ojala
, Tuula Manninen
, Aino Mutka
, Kaisa Ylänen
, Otto Rahkonen
, Tuija Poutanen
, Laura Martelius
, Reena Kumari
, Helena Hinterding
, Virginia Brilhante
, Simo Ojanen
, Pekka Lappalainen
, Juha Koskenvuo
, Christopher J. Carroll
, Velia M. Fowler
, Carol C. Gregorio^*
, Anu Suomalainen^*

^*Tämän työn vastaava kirjoittaja

Tutkimustuotos: Artikkeli › Tieteellinen › vertaisarvioitu

9 Sitaatiot (Scopus)

25 Lataukset (Pure)

Abstrakti

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 TMOD1^R189W and its affinity for actin. Cardiomyocytes expressing GFP-TMOD1^R189W demonstrated longer thin filaments than GFP-TMOD1^wt-expressing cells, resulting in compromised filament length regulation. Furthermore, TMOD1^R189W 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.

Alkuperäiskieli	Englanti
Artikkeli	7
Julkaisu	Communications Biology
Vuosikerta	7
Numero	1
DOI - pysyväislinkit	https://doi.org/10.1038/s42003-023-05670-9
Tila	Julkaistu - tammik. 2024
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Rahoitus

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.

Rahoittajat	Rahoittajan numero
Maud Kuistila Foundation, Foundation for Pediatric Research Finland
National Institutes of Health	R01HL164644, R01HL123078
American Heart Association	19POST34450023
Helsingin yliopisto
Alfred Kordelinin Säätiö
Academy of Finland
Suomen Kulttuurirahasto
Jane ja Aatos Erkon Säätiö
Sydäntutkimussäätiö
Sigrid Juséliuksen Säätiö
Otto A. Malm Lahjoitusrahasto

Julkaisufoorumi-taso

Jufo-taso 1

!!ASJC Scopus subject areas

Medicine (miscellaneous)
Yleinen biokemia, genetiikka ja molekyylibiologia
Yleiset maatalous- ja biotieteet

Pääsy asiakirjaan

10.1038/s42003-023-05670-9Lisenssi: CC BY

s42003-023-05670-9Final published version, 2,34 MBLisenssi: CC BY

https://urn.fi/URN:NBN:fi:tuni-202406187275Lisenssi: CC BY

Siteeraa tätä

Vasilescu, C., Colpan, M., Ojala, T. H., 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, C. J., Fowler, V. M., Gregorio, C. C., & Suomalainen, A. (2024). Recessive TMOD1 mutation causes childhood cardiomyopathy. Communications Biology, 7(1), Artikkeli 7. https://doi.org/10.1038/s42003-023-05670-9

@article{061b1473ef424d5b9878d6c7d3fdd7a2,

title = "Recessive TMOD1 mutation causes childhood cardiomyopathy",

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{\textquoteright}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.",

author = "Catalina Vasilescu and Mert Colpan and Ojala, \{Tiina H.\} and Tuula Manninen and Aino Mutka and Kaisa Yl{\"a}nen and Otto Rahkonen and Tuija Poutanen and Laura Martelius and Reena Kumari and Helena Hinterding and Virginia Brilhante and Simo Ojanen and Pekka Lappalainen and Juha Koskenvuo and Carroll, \{Christopher J.\} and Fowler, \{Velia M.\} and Gregorio, \{Carol C.\} and Anu Suomalainen",

note = "Publisher Copyright: {\textcopyright} 2024, The Author(s).",

year = "2024",

month = jan,

doi = "10.1038/s42003-023-05670-9",

language = "English",

volume = "7",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Springer",

number = "1",

}

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', Communications Biology, Vuosikerta 7, Nro 1, 7. https://doi.org/10.1038/s42003-023-05670-9

TY - JOUR

T1 - Recessive TMOD1 mutation causes childhood cardiomyopathy

AU - Vasilescu, Catalina

AU - Colpan, Mert

AU - Ojala, Tiina H.

AU - Manninen, Tuula

AU - Mutka, Aino

AU - Ylänen, Kaisa

AU - Rahkonen, Otto

AU - Poutanen, Tuija

AU - Martelius, Laura

AU - Kumari, Reena

AU - Hinterding, Helena

AU - Brilhante, Virginia

AU - Ojanen, Simo

AU - Lappalainen, Pekka

AU - Koskenvuo, Juha

AU - Carroll, Christopher J.

AU - Fowler, Velia M.

AU - Gregorio, Carol C.

AU - Suomalainen, Anu

PY - 2024/1

Y1 - 2024/1

N2 - 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.

AB - 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.

U2 - 10.1038/s42003-023-05670-9

DO - 10.1038/s42003-023-05670-9

M3 - Article

C2 - 38168645

AN - SCOPUS:85181258121

SN - 2399-3642

VL - 7

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 7

ER -

Recessive TMOD1 mutation causes childhood cardiomyopathy

Abstrakti

Rahoitus

Julkaisufoorumi-taso

!!ASJC Scopus subject areas

Pääsy asiakirjaan

Sormenjälki

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