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Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to

Shawna M Pyott1, Ulrike Schwarze, Helena E Christiansen

  • 1Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA.

Human Molecular Genetics
|February 2, 2011
PubMed

Insights

Recessive mutations in PPIB, CRTAP, and LEPRE1 genes cause osteogenesis imperfecta (OI). PPIB mutations lead to severe collagen defects, impacting procollagen folding and trimer formation in the endoplasmic reticulum.

Area of Science:

  • Biochemistry
  • Genetics
  • Molecular Biology

Background:

  • Osteogenesis imperfecta (OI) is a group of genetic disorders characterized by bone fragility.
  • Recessive mutations in CRTAP, LEPRE1, and PPIB genes cause severe forms of OI, affecting type I procollagen synthesis.
  • These genes encode proteins CRTAP, prolyl 3-hydroxylase 1 (P3H1), and cyclophilin B (CYPB), which form a complex in the rough endoplasmic reticulum (RER) essential for prolyl 3-hydroxylation of type I procollagen.

Purpose of the Study:

  • To investigate the role of cyclophilin B (CYPB), encoded by the PPIB gene, in the pathogenesis of osteogenesis imperfecta (OI).
  • To characterize the molecular defects in type I procollagen processing caused by PPIB mutations.

Main Methods:

  • Analysis of mutations in the PPIB gene in three individuals with OI.
  • Cultured dermal fibroblasts from affected individuals were used to study type I procollagen production and processing.
  • Assessment of procollagen modification, trimerization, RER accumulation, and binding to protein disulfide isomerase (PDI) and prolyl 4-hydroxylase 1 (P4H1).

Main Results:

  • Mutations in PPIB were identified in individuals with OI, leading to the production of overmodified type I procollagen molecules.
  • Proα1(I) chains exhibited delayed trimer assembly, and abnormal procollagen accumulated in the RER, binding to PDI and P4H1.
  • The extent of procollagen accumulation and PDI/P4H1 binding was greatest in PPIB-deficient cells compared to cells with CRTAP or LEPRE1 mutations.

Conclusions:

  • CYPB (PPIB) plays a crucial role not only in prolyl peptide bond isomerization for helix formation but also in the folding of the C-terminal propeptide and subsequent trimer formation.
  • Prolyl cis-trans isomerase activity is essential for proper folding of proline-rich regions in the C-terminal propeptide, facilitating proα chain association.
  • These findings suggest a sequential order of action for CRTAP, P3H1, and CYPB in procollagen biosynthesis and the pathogenesis of OI.

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