TMEM53 as an outer nuclear membrane regulator of cranial and tubular bone formation in craniotubular dysplasia.

Transmembrane protein 53 (TMEM53) is an outer nuclear membrane protein that plays a crucial role in maintaining skeletal homeostasis. Pathogenic variants in TMEM53 have been identified as the genetic cause of craniotubular dysplasia, Ikegawa type (CTDI), a rare form of sclerosing bone dysplasia characterized by skull hyperostosis, cranial deformities, and increased bone density. To date, the causal association of bi-allelic pathogenic variants of TMEM53 in CTDI has been identified in 14 patients from eight unrelated families. Mechanistically, TMEM53 negatively regulates BMP-SMAD signaling by restricting the nuclear import of phosphorylated SMAD1/5/9, thereby modulating osteoblast differentiation and bone formation. This review summarizes the current understanding of TMEM53 function and the consequences of its deficiency. We aim to clarify genotype-phenotype correlations, outline therapeutic prospects for CTDI, and explore the distinct mechanisms underlying cranial and tubular bone formation.