Recessive TMOD1 mutation causes childhood cardiomyopathy

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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.
Funding Information
  • Jane ja Aatos Erkon Säätiö
  • Sigrid Juséliuksen Säätiö
  • University of Helsinki | Helsingin Yliopiston Tiedesäätiö
  • Research Council of Finland
  • Finnish Cultural Foundation | Etelä-Karjalan Rahasto
  • Alfred Kordelinin Säätiö
  • Maud Kuistilan Muistosäätiö
  • Lastentautien Tutkimussäätiö
  • U.S. Department of Health & Human Services | National Institutes of Health (R01HL123078, R01HL164644)
  • U.S. Department of Health & Human Services | National Institutes of Health
  • American Heart Association (19POST34450023)

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