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<p>Transmembrane protein 53 (TMEM53) is an outer nuclear membrane protein that plays a crucial role in maintaining skeletal homeostasis. Pathogenic variants in <i>TMEM53</i> 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 <i>TMEM53</i> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年12月17日

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  • Kaitao Ren,
  • Yiyang Fu,
  • Jinhui Zhu,
  • Wanqi Liu,
  • Yuxin Han,
  • Shuying Zhang,
  • Xiaorui Zhang,
  • Mingyue Chen,
  • Congcong Xia,
  • Kexin Sun,
  • Dan Xiao,
  • Yuan Liu,
  • Lin Wang,
  • Rong Qiang,
  • Chisa Shukunami,
  • Katta M. Girisha,
  • Shiro Ikegawa,
  • Long Guo

摘要

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.