Key result
The TBX5 R264K variant acts as a disease modifier, with homozygous mice developing compensated dilated cardiomyopathy and significantly reduced fractional shortening (34.2% vs 39.6%) compared to wild-type mice.
Why the study?
The pathogenicity of the TBX5 R264K variant, found over-represented in cardiomyopathy patients outside the T-box domain, had not been confirmed by functional analyses.
Does the TBX5 R264K variant cause dilated cardiomyopathy in a mouse model?
Does the TBX5 R264K variant cause dilated cardiomyopathy in a mouse model?
Absolute Event Rate: 34.2% vs 39.6%
p-value: p=<0.05
The TBX5 R264K variant induces compensated dilated cardiomyopathy in mice independently of the T-box domain pathway, suggesting a pathogenic role in some cardiomyopathy patients.
Tbx5 R264K supports compensated DCM in mice; hypothesis-generating for human cardiomyopathy without practice change.
BACKGROUND: TBX5 is a transcription factor that has an important role in development of heart. TBX5 variants in the region encoding the T-box domain have been shown to cause cardiac defects, such as atrial septal defect or ventricular septal defect, while TBX5 variants have also been identified in a few cardiomyopathy patients and considered causative. We identified a TBX5 variant (c.791G>A, p.Arg264Lys), that is over-represented in cardiomyopathy patients. This variant is located outside of the T-box domain, and its pathogenicity has not been confirmed by functional analyses. OBJECTIVE: To investigate whether the TBX5 R264K is deleterious and could contribute to the pathogenesis of cardiomyopathy. METHODS AND RESULTS: We developed mice expressing Tbx5 R264K. Mice homozygous for this variant displayed compensated dilated cardiomyopathy; mild decreased fractional shortening, dilatation of the left ventricle, left ventricular wall thinning and increased heart weight without major heart structural disorders. There was no difference in activation of the ANF promotor, a transcriptional target of Tbx5, compared to wild-type. However, analysis of RNA isolated from left ventricular samples showed significant increases in the expression of Acta1 in left ventricle with concomitant increases in the protein level of ACTA1. CONCLUSIONS: Mice homozygous for Tbx5 R264K showed compensated dilated cardiomyopathy. Thus, TBX5 R264K may have a significant pathogenic role in some cardiomyopathy patients independently of T-box domain pathway.
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Miyao et al. (2020) studied Dilated cardiomyopathy and left ventricular non compaction (n=233). TBX5 R264K variant vs. Wild-type TBX5 was evaluated on Fractional shortening (%) in young adult mice (p=<0.05). The TBX5 R264K variant acts as a disease modifier, with homozygous mice developing compensated dilated cardiomyopathy and significantly reduced fractional shortening (34.2% vs 39.6%) compared to wild-type mice.
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