Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
Department of Clinical Genome Analysis, Medical Genome Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Nat Commun. 2021 Apr 6;12(1):2046. doi: 10.1038/s41467-021-22340-8.
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.
骨形成是一种受多种信号和复杂机制调节的遗传特征。其异常表现在各种疾病中，包括硬化性骨病（SBD）。对导致 SBD 的基因的探索显著提高了我们对调节骨形成机制的理解。在这里，我们在四个独立的家族中发现了一种以前未知的 SBD，其原因是 TMEM53 的双等位基因功能丧失致病性变异，该基因编码核膜跨膜蛋白。Tmem53 小鼠重现了人类骨骼表型。使用 Tmem53 小鼠的原代细胞和 TMEM53 敲除细胞系进行的分子病理生理学分析表明，TMEM53 通过阻止 BMP2 激活的 Smad 蛋白的细胞质-核易位来抑制成骨细胞谱系细胞中的 BMP 信号。患者中的致病性变异会损害 TMEM53 介导的阻断作用，从而导致过度激活的 BMP 信号，促进骨形成，并导致 SBD 表型。我们的结果确立了一种以前未报道的 SBD 实体（颅管状发育不良，池上型），并有助于更好地理解 BMP 信号和骨形成的调节。
