MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

Nat Commun. 2016 Jul 6:7:11920. doi: 10.1038/ncomms11920.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / genetics
  • Activating Transcription Factor 6 / metabolism
  • Adult
  • Aged
  • Cell Differentiation
  • Cell Membrane / metabolism
  • Cell Membrane / pathology*
  • Collagen Type I / deficiency
  • Collagen Type I / genetics*
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Gene Expression Regulation
  • Genes, Recessive
  • Humans
  • Hydroxylation
  • Male
  • Metalloendopeptidases / genetics*
  • Metalloendopeptidases / metabolism
  • Middle Aged
  • Mutation, Missense*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Osteoblasts / metabolism*
  • Osteoblasts / pathology
  • Osteogenesis Imperfecta / genetics*
  • Osteogenesis Imperfecta / metabolism
  • Osteogenesis Imperfecta / pathology
  • Pedigree
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / genetics
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / metabolism
  • Proteolysis
  • Severity of Illness Index
  • Sterol Regulatory Element Binding Proteins / genetics
  • Sterol Regulatory Element Binding Proteins / metabolism

Substances

  • ATF6 protein, human
  • Activating Transcription Factor 6
  • CREB3L1 protein, human
  • Collagen Type I
  • Cyclic AMP Response Element-Binding Protein
  • Nerve Tissue Proteins
  • Sterol Regulatory Element Binding Proteins
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
  • lysyl hydroxylase 1, human
  • Metalloendopeptidases
  • MBTPS2 protein, human