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

Journal of Human Genetics (2025)Cite this article

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Abstract

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.

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Fig. 1: Roles of TMEM53 in cell cycle and osteogenesis.

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Acknowledgements

We thank the patients and their families for their help to the study.

Funding

This study was supported by National Natural Science Foundation of China (Grant No. 82471900, L.G.) (Grant No. 82201865, Y.L.) (Grant No. 32400088, D.X.), Supporting Program of Innovation Capability Shaanxi Province (2024CX-GXPT-40, L.G.), Young Talent Support Plan from Xi’an Jiaotong University (YX6J033, L.G.), and Provincial Talent Research Support Fund (71240000000131, L.G.), Shaanxi Provincial Project for Innovation Capacity Improvement of Health Research (2024PT-03, R.Q.), and Provincial Key Industry Innovation Chain (2024SF-ZDCYL-04-05, R.Q.), Department of Genetics, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China First People's Hospital of Yunnan Province, Kunming, China (No.2025XBYSKF012) Grant for NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China First People’s Hospital of Yunnan Province (L.W.).

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Authors and Affiliations

  1. Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China

    Kaitao Ren, Yiyang Fu, Jinhui Zhu, Wanqi Liu, Yuxin Han, Shuying Zhang, Xiaorui Zhang, Mingyue Chen, Congcong Xia, Kexin Sun & Long Guo

  2. Center of Medical Genetics, Northwest Women’s and Children’s Hospital & the Affiliated Northwest Women’s and Children’s Hospital of Xi’an Jiaotong University, Xi’an, China

    Dan Xiao, Yuan Liu, Lin Wang, Rong Qiang & Long Guo

  3. Department of Molecular Biology and Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

    Chisa Shukunami

  4. Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

    Katta M. Girisha

  5. Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    Shiro Ikegawa

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  1. Kaitao Ren
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  2. Yiyang Fu
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  3. Jinhui Zhu
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Contributions

Long Guo and Shiro Ikegawa conceived and designed the review. Kaitao Ren drafted the initial manuscript; all authors contributed to subsequent revisions and critically reviewed the content. All authors approved the final version for submission.

Corresponding author

Correspondence to Long Guo.

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Ren, K., Fu, Y., Zhu, J. et al. TMEM53 as an outer nuclear membrane regulator of cranial and tubular bone formation in craniotubular dysplasia. J Hum Genet (2025). https://doi.org/10.1038/s10038-025-01443-w

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