Recessive Osteogenesis Imperfecta: Prevalence and Pathophysiology of Collagen Prolyl-3-Hydroxylation Complex Defects

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Osteogenesis Imperfecta (OI) is a clinically and genetically heterogeneous heritable bone dysplasia occurring in 1/15,000-20,000 births. OI is a collagen-related disorder, with the more prevalent dominant forms caused by defects in the genes encoding the α1 and α2 chains of type I collagen (COL1A1 and COL1A2). Rare recessive forms of OI are caused by deficiency of proteins required for collagen post-translational modifications or folding. We identified deficiency of components of the ER-resident collagen prolyl 3-hydroxylase (P3H) complex as a cause of recessive OI. The P3H complex, consisting of prolyl 3-hydroxylase 1 (P3H1), cartilage-associated protein (CRTAP) and cyclophilin B/peptidyl-prolyl isomerase B (CyPB/PPIB), modifies the α1(I) P986 and α2(I) P707 residues of type I collagen. The most common P3H complex defects occur in LEPRE1, the gene encoding P3H1, and over one-third of these cases are due to a founder mutation we identified among individuals of West African and African American descent. Our screening of contemporary cohorts revealed that 0.4% of African Americans and nearly 1.5% of West Africans are carriers for this mutation, predicting a West African frequency of recessive OI due to homozygosity for this mutation at 1/18,260 births, equal to de novo dominant OI. Furthermore, haplotype analysis of affected families was consistent with a single founder for this mutation, occurring 650-900 years ago (1100-1350 C.E.). Patients deficient in P3H1 and CRTAP have consistent bone phenotypes and collagen biochemistry. However, the rare cases of CyPB deficiency have variable findings distinct from P3H1/CRTAP. To clarify the OI mechanism of CyPB deficiency, we generated a Ppib knock-out mouse. In the absence of CyPB, only residual collagen prolyl 3-hydroxylation is detectable in KO cells and tissues. The delay in collagen folding in KO cells is further increased upon cyclophilin inhibition, supporting CyPB's role as an isomerase and the presence of redundancy for collagen ER PPIases. Site-specific alterations of collagen post-translational modification, particularly at residues involved in helical crosslinking, suggest that CyPB is critical to the function of collagen hydroxylases, especially LH1. Thus our studies indicate novel roles for CyPB, separate from the P3H complex, which directly and indirectly regulate collagen biosynthesis and bone development.