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

Long Guo (), Aritoshi Iida, Gandham SriLakshmi Bhavani, Kalpana Gowrishankar, Zheng Wang, Jing-yi Xue, Juan Wang, Noriko Miyake, Naomichi Matsumoto, Takanori Hasegawa, Yusuke Iizuka, Masashi Matsuda, Tomoki Nakashima, Masaki Takechi, Sachiko Iseki, Shinsei Yambe, Gen Nishimura, Haruhiko Koseki, Chisa Shukunami, Katta M. Girisha () and Shiro Ikegawa ()
Additional contact information
Long Guo: RIKEN Center for Integrative Medical Sciences
Aritoshi Iida: RIKEN Center for Integrative Medical Sciences
Gandham SriLakshmi Bhavani: Manipal Academy of Higher Education
Kalpana Gowrishankar: Kanchi Kamakoti CHILDS Trust Hospital
Zheng Wang: RIKEN Center for Integrative Medical Sciences
Jing-yi Xue: RIKEN Center for Integrative Medical Sciences
Juan Wang: RIKEN Center for Integrative Medical Sciences
Noriko Miyake: Yokohama City University Graduate School of Medicine
Naomichi Matsumoto: Yokohama City University Graduate School of Medicine
Takanori Hasegawa: RIKEN Center for Integrative Medical Sciences
Yusuke Iizuka: RIKEN Center for Integrative Medical Sciences
Masashi Matsuda: RIKEN Center for Integrative Medical Sciences
Tomoki Nakashima: Tokyo Medical and Dental University
Masaki Takechi: Tokyo Medical and Dental University
Sachiko Iseki: Tokyo Medical and Dental University
Shinsei Yambe: Hiroshima University
Gen Nishimura: RIKEN Center for Integrative Medical Sciences
Haruhiko Koseki: RIKEN Center for Integrative Medical Sciences
Chisa Shukunami: Hiroshima University
Katta M. Girisha: Manipal Academy of Higher Education
Shiro Ikegawa: RIKEN Center for Integrative Medical Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22340-8

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