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Translational Surprises in Human Hearts

Commented article by the ESC Working Group on Myocardial Function

Pathophysiology and Mechanisms
Pathophysiology and Mechanisms
Basic Science - Cardiac Diseases - Cardiomyopathies


An international team of researchers led by the Max Delbruck Center Berlin (Germany) reports novel proteins made by the ribosomes in cardiomyocytes of healthy people and patients with dilated cardiomyopathy (DCM). While transcriptional processes are relatively well understood, there are still many questions about the translation of mRNA into protein in the ribosomes. Using ribosome profiling (ribo-seq), the team determined for the first time in human heart tissue, which proteins are formed during translation. They discovered a whole series of tiny, previously unknown ‘microproteins’ encoded by RNAs thought to be non-coding so far. Many of them were evolutionarily young substances that could not be detected, eg in mouse hearts. Most mini-proteins appeared to be used for energy production in the mitochondria.


In order to detect possible differences in the translatome between diseased and healthy hearts, the team examined tissue samples of 65 patients with DCM and 15 non-failing heart tissues. The DCM samples included many with a truncating mutation in TTN, the main cardiomyopathy gene coding for the sarcomere protein titin (1, 2). Interestingly, they observed that sometimes the ribosomes can ignore the stop signal due to the TTN truncation, such that near-wildtype proteins are being made. These findings may change our view on how gene truncations cause cardiomyopathy and may raise new possibilities for the treatment of these patients.

References


  1. Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 366(7):619-28, 2012.
  2. Schafer S, de Marvao A, Adami E, Fiedler LR, Ng B, Khin E, Rackham OJ, van Heesch S, Pua CJ, Kui M, Walsh R, Tayal U, Prasad SK, Dawes TJ, Ko NS, Sim D, Chan LL, Chin CW, Mazzarotto F, Barton PJ, Kreuchwig F, de Kleijn DP, Totman T, Biffi C, Tee N, Rueckert D, Schneider V, Faber A, Regitz-Zagrosek V, Seidman JG, Seidman CE, Linke WA, Kovalik JP, O'Regan D, Ware JS, Hubner N, Cook SA. Titin-truncating variants affect heart function in disease cohorts and the general population. Nat Genet 49(1):46-53, 2017.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.