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Null mutations in cartilage-associated protein ( CRTAP ) and prolyl 3-hydroxylase 1 (P3H1/ LEPRE1)  cause types VII and VIII OI, respectively, two novel recessive forms of osteogenesis imperfecta (OI) with severe to lethal bone dysplasia and overmodification of the type I collagen helical region. CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic reticulum (ER) which 3-hydroxylates the Pro986 residue of α1(I) and α1(II) collagen chains. We investigated the interaction of complex components in fibroblasts from types VII and VIII OI patients. Both CRTAP and P3H1 are absent or reduced on western blots and by immunofluorescence microscopy in cells containing null mutations in either gene. Levels of  LEPRE1  or  CRTAP  transcripts, however, are normal in  CRTAP - or  LEPRE1 -null cells, respectively. Stable transfection of a  CRTAP  or  LEPRE1  expression construct into cells with null mutations for the transfected cDNA restored both CRTAP and P3H1 protein levels. Normalization of collagen helical modification in transfected  CRTAP -null cells demonstrated that the restored proteins functioned effectively as a complex. These data indicate that CRTAP and P3H1 are mutually stabilized in the collagen prolyl 3-hydroxylation complex. CyPB levels were unaffected by mutations in either  CRTAP  or  LEPRE1 . Proteasomal inhibitors partially rescue P3H1 protein in  CRTAP -null cells. In  LEPRE1 -null cells, secretion of CRTAP is increased compared with control cells and accounts for 15–20% of the decreased CRTAP detected in cells. Thus, mutual stabilization of P3H1 and CRTAP in the ER collagen modification complex is an underlying mechanism for the overlapping phenotype of types VII and VIII OI.

Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in the endoplasmic reticulum collagen prolyl 3-hydroxylation complex