Formation of a TBX20-CASZ1 protein complex is protective against dilated cardiomyopathy and critical for cardiac homeostasis.

TitleFormation of a TBX20-CASZ1 protein complex is protective against dilated cardiomyopathy and critical for cardiac homeostasis.
Publication TypeJournal Article
Year of Publication2017
AuthorsKennedy, L, Kaltenbrun, E, Greco, TM, Temple, B, Herring, LE, Cristea, IM, Conlon, FL
JournalPLoS Genet
Date Published2017 Sep
KeywordsAnimals, Cardiomyopathy, Dilated, DNA-Binding Proteins, Heart Failure, Humans, Mice, Mutation, Proteomics, T-Box Domain Proteins, Transcription Factors

<p>By the age of 40, one in five adults without symptoms of cardiovascular disease are at risk for developing congestive heart failure. Within this population, dilated cardiomyopathy (DCM) remains one of the leading causes of disease and death, with nearly half of cases genetically determined. Though genetic and high throughput sequencing-based approaches have identified sporadic and inherited mutations in a multitude of genes implicated in cardiomyopathy, how combinations of asymptomatic mutations lead to cardiac failure remains a mystery. Since a number of studies have implicated mutations of the transcription factor TBX20 in congenital heart diseases, we investigated the underlying mechanisms, using an unbiased systems-based screen to identify novel, cardiac-specific binding partners. We demonstrated that TBX20 physically and genetically interacts with the essential transcription factor CASZ1. This interaction is required for survival, as mice heterozygous for both Tbx20 and Casz1 die post-natally as a result of DCM. A Tbx20 mutation associated with human familial DCM sterically interferes with the TBX20-CASZ1 interaction and provides a physical basis for how this human mutation disrupts normal cardiac function. Finally, we employed quantitative proteomic analyses to define the molecular pathways mis-regulated upon disruption of this novel complex. Collectively, our proteomic, biochemical, genetic, and structural studies suggest that the physical interaction between TBX20 and CASZ1 is required for cardiac homeostasis, and further, that reduction or loss of this critical interaction leads to DCM. This work provides strong evidence that DCM can be inherited through a digenic mechanism.</p>

Alternate JournalPLoS Genet
PubMed ID28945738
PubMed Central IDPMC5629033
Grant ListP30 CA016086 / CA / NCI NIH HHS / United States
R01 HL112618 / HL / NHLBI NIH HHS / United States
T32 HL069768 / HL / NHLBI NIH HHS / United States
R01 GM114141 / GM / NIGMS NIH HHS / United States
R01 HL127640 / HL / NHLBI NIH HHS / United States