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

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

  • Nat Commun. 2021 Apr 6;12(1):2046. doi: 10.1038/s41467-021-22340-8.
Long Guo 1,  Aritoshi Iida 2 3,  Gandham SriLakshmi Bhavani 4,  Kalpana Gowrishankar 5,  Zheng Wang 2 6,  Jing-Yi Xue 2 7,  Juan Wang 2 8,  Noriko Miyake 7,  Naomichi Matsumoto 7,  Takanori Hasegawa 9,  Yusuke Iizuka 9,  Masashi Matsuda 9,  Tomoki Nakashima 10,  Masaki Takechi 11,  Sachiko Iseki 11,  Shinsei Yambe 12,  Gen Nishimura 2,  Haruhiko Koseki 9,  Chisa Shukunami 12,  Katta M Girisha 13,  Shiro Ikegawa 14
Affiliations

Affiliations

  • 1 Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan. [email protected].
  • 2 Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
  • 3 Department of Clinical Genome Analysis, Medical Genome Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
  • 4 Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.
  • 5 Kanchi Kamakoti CHILDS Trust Hospital, Tamil Nadu, India.
  • 6 Department of Medical Genetics, Institute of Basic Medical Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
  • 7 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 8 Department of Ultrasound, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
  • 9 Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • 10 Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
  • 11 Department of Molecular Craniofacial Embryology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
  • 12 Department of Molecular Biology and Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
  • 13 Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India. [email protected].
  • 14 Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan. [email protected].
PMID: 33824347 DOI: 10.1038/s41467-021-22340-8
Abstract

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 of the mechanisms that regulate bone formation. Here, we discover a previously unknown type of SBD in four independent families caused by bi-allelic loss-of-function pathogenic variants in TMEM53, which encodes a nuclear envelope transmembrane protein. Tmem53-/- mice recapitulate the human skeletal phenotypes. Analyses of the molecular pathophysiology using the primary cells from the Tmem53-/- mice and the TMEM53 knock-out cell lines indicates that TMEM53 inhibits BMP signaling in osteoblast lineage cells by blocking cytoplasm-nucleus translocation of BMP2-activated Smad proteins. Pathogenic variants in the patients impair the TMEM53-mediated blocking effect, thus leading to overactivated BMP signaling that promotes bone formation and contributes to the SBD phenotype. Our results establish a previously unreported SBD entity (craniotubular dysplasia, Ikegawa type) and contribute to a better understanding of the regulation of BMP signaling and bone formation.

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