Due to the phenotypic similarity between the Tmem53 mutant mice and the individuals with TMEM53 pathologic variants, it is reasonable to conclude that the previously unknown type of skeletal dysplasia is causally associated with loss-of-function of TMEM53 in regulating the cytoplasm–nucleus translocation of phosphorylated SMAD1/5/9 (Fig. 5m). Here, TMEM53 is linked to skeletal dysplasia.