MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 27380894.
- Also identified by DOI 10.1038/ncomms11920 and PMC identifier 4935805.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- Cell Membrane
- Collagen Type I
- Metalloendopeptidases
- Mutation, Missense
- Osteoblasts
- Osteogenesis Imperfecta