PPIB Mutations Cause Severe Osteogenesis Imperfecta

Abstract

Deficiency of cartilage-associated protein (CRTAP) or prolyl 3-hydroxylase 1(P3H1) has been reported in autosomal-recessive lethal or severe osteogenesis imperfecta (OI). CRTAP, P3H1, and cyclophilin B (CyPB) form an intracellular collagen-modifying complex that 3-hydroxylates proline at position 986 (P986) in the alpha1 chains of collagen type I. This 3-prolyl hydroxylation is decreased in patients with CRTAP and P3H1 deficiency. It was suspected that mutations in the PPIB gene encoding CyPB would also cause OI with decreased collagen 3-prolyl hydroxylation. To our knowledge we present the first two families with recessive OI caused by PPIB gene mutations. The clinical phenotype is compatible with OI Sillence type II-B/III as seen with COL1A1/2, CRTAP, and LEPRE1 mutations. The percentage of 3-hydroxylated P986 residues in patients with PPIB mutations is decreased in comparison to normal, but it is higher than in patients with CRTAP and LEPRE1 mutations. This result and the fact that CyPB is demonstrable independent of CRTAP and P3H1, along with reported decreased 3-prolyl hydroxylation due to deficiency of CRTAP lacking the catalytic hydroxylation domain and the known function of CyPB as a cis-trans isomerase, suggest that recessive OI is caused by a dysfunctional P3H1/CRTAP/CyPB complex rather than by the lack of 3-prolyl hydroxylation of a single proline residue in the alpha1 chains of collagen type I.

Genetic epidemiology, prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] On the contrary, here 15/32 families with no mutation in collagen I had a typical type I phenotype, and 25 additional families were excluded on the basis of a negative sequencing result in combination with an unclear clinical phenotype. These individuals may have a COL1A1 null allele caused by a non-exonic mutation missed here; however, another OI-related gene might be causative in some instances.…”

“…Dominant mutations in collagen type I are generally stated to be responsible for 90% of cases, while a plethora of other genes have been associated with non-collagen OI in recent years. [1][2][3][4][5][6][7][8][9][10][11][12][13] Collagen type I, encoded by COL1A1 and COL1A2, constitutes 85% of the organic matrix in skeletal tissue, and forms a framework for mineral deposition, rendering bone the tensile properties needed to withstand torsion and bending powers. Procollagen is a heterotrimer, with a helical 1014-amino acid-long central stretch of two α1-and one α2-chains, which is flanked by globular N-and C-terminal regions.…”

Osteogenesis imperfecta

“…3) result in a more variable clinical and biochemical phenotype that overlaps with that caused by CRTAP and P3H1 mutations, except for the absence of rhizomelia 58,61-63 . In two patients, a moderate osteogenesis imperfecta phenotype was described 64 , which was associated with normal 3 hydroxy lation of proline 986 of the α1(I) chain and normal heli cal folding, whereas in others, hydroxylation of proline 986 of the α1(I) chain was reduced to a lesser extent than patients with CRTAP and P3H1 deficiency, and colla gen overmodification was observed 58 . These findings suggest that collagen modification is dependent on the PPIB mutation.…”

Bone Material Properties in Osteogenesis Imperfecta

“…Type 1 collagen a2 chain Yes Mild-lethal OI (18) High bone mass in C-propeptide cleavage site defects (61) Collagen folding PPIB Cyclophilin B Yes Moderate-lethal OI (112) …”