TGFBR1 mutations associated with Loeys-Dietz syndrome are inactivating

Abstract

To assess the effect of Loeys-Dietz syndrome (LDS) mutations affecting TGFΒR1 a selection of seven disease-associated amino acid substitutions were introduced into wild type TGFβR1 and constitutively active TGFβR1^T204D. Receptor function was tested by co-transfection with a luciferase reporter or EGFP-tagged SMAD2 in HEK293 cells. All of the mutations were found to be inactivating for canonical TGF-β signaling. Differences in residual activity were not found to correlate with disease subtype. In co-transfection experiments with equal amounts wild-type receptor, the LDS mutations were found to confer a modest dominant negative effect. These results are discussed in relation to LDS and the related Marfan syndrome.

Keywords::

• Loeys-Dietz syndrome
• Marfan Syndrome
• Transforming Growth Factor-β
• TGF-β
• TGFBR1
• Aortic aneurysm

Acknowledgement

This work was supported by funding from Curekids New Zealand.

Declaration of interest

The authors have no interests to declare.