Open AccessThe distal arthrogryposis‐linked p.R63C variant promotes the stability and nuclear accumulation of TNNT3
Author(s) -
Lu Jinfang,
Li Huanzheng,
Zhang He,
Lin Zhengxiu,
Xu Chenyang,
Xu Xueqin,
Hu Lin,
Luan Zhaotang,
Lou Yongliang,
Tang Shaohua
Publication year - 2021
Publication title -
journal of clinical laboratory analysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.536
H-Index - 50
eISSN - 1098-2825
pISSN - 0887-8013
DOI - 10.1002/jcla.24089
Subject(s) - skeletal muscle , sanger sequencing , biology , arthrogryposis , missense mutation , lamin , proteasome , muscle contracture , ubiquitin , endocrinology , nucleus , mutation , genetics , microbiology and biotechnology , anatomy , gene
Background Distal arthrogryposis (DA) is comprised of a group of rare developmental disorders in muscle, characterized by multiple congenital contractures of the distal limbs. Fast skeletal muscle troponin‐T (TNNT3) protein is abundantly expressed in skeletal muscle and plays an important role in DA. Missense variants in TNNT3 are associated with DA, but few studies have fully clarified its pathogenic role. Methods Sanger sequencing was performed in three generation of a Chinese family with DA. To determine how the p.R63C variant contributed to DA, we identified a variant in TNNT3 (NM_006757.4): c.187C>T (p.R63C). And then we investigated the effects of the arginine to cysteine substitution on the distribution pattern and the half‐life of TNNT3 protein. Results The protein levels of TNNT3 in affected family members were 0.8‐fold higher than that without the disorder. TNNT3 protein could be degraded by the ubiquitin‐proteasome complex, and the p.R63C variant did not change TNNT3 nuclear localization, but significantly prolonged its half‐life from 2.5 to 7 h, to promote its accumulation in the nucleus. Conclusion The p.R63C variant increased the stability of TNNT3 and promoted nuclear accumulation, which suggested its role in DA.