Deficiency of TMEM53 causes a previously unknown sclerosing bone disorder by dysregulation of BMP-SMAD signaling.

摘要: Bone formation represents a heritable trait regulated by many signals and complex mechanisms. Its abnormalities manifest themselves in various diseases, including sclerosing bone disorder (SBD). Exploration of genes that cause SBD has significantly improved our understanding the mechanisms regulate formation. Here, we discover previously unknown type four independent families caused bi-allelic loss-of-function pathogenic variants TMEM53, which encodes nuclear envelope transmembrane protein. Tmem53-/- mice recapitulate human skeletal phenotypes. Analyses molecular pathophysiology using primary cells from TMEM53 knock-out cell lines indicates inhibits BMP signaling osteoblast lineage blocking cytoplasm-nucleus translocation BMP2-activated Smad proteins. Pathogenic patients impair TMEM53-mediated effect, thus leading to overactivated promotes contributes phenotype. Our results establish unreported entity (craniotubular dysplasia, Ikegawa type) contribute better regulation