Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/ncomms11920
Keywords
-
Categories
Funding
- Thailand Research Fund [RTA56800003, TRG5480013]
- Chulalongkorn Academic Advancement
- Swiss National Research Foundation (SNF Grant) [310030_138288]
- NIH [AR037318, HD070394]
- NICHD Intramural Funds
- Swiss National Science Foundation (SNF) [310030_138288] Funding Source: Swiss National Science Foundation (SNF)
Ask authors/readers for more resources
Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available