More importantly, phosphorylation of Smad2 and Smad3 upon TGFβ stimulation was significantly attenuated in TD cells (Figure 2B), and the total protein expression level of not only Smad2 and Smad3 but also Smad4, a key co-factor for Smad2/3 nuclear translocation [20], was markedly reduced in TD cells (Figure 2C). Here, SMAD4 is linked to thanatophoric dysplasia.