PPIB Mutations Cause Severe Osteogenesis Imperfecta

• Published in: American journal of human genetics 2009-10, Vol.85 (4), p.521-527
• Main Authors: van Dijk, Fleur S., Nesbitt, Isabel M., Zwikstra, Eline H., Nikkels, Peter G.J., Piersma, Sander R., Fratantoni, Silvina A., Jimenez, Connie R., Huizer, Margriet, Morsman, Alice C., Cobben, Jan M., van Roij, Mirjam H.H., Elting, Mariet W., Verbeke, Jonathan I.M.L., Wijnaendts, Liliane C.D., Shaw, Nick J., Högler, Wolfgang, McKeown, Carole, Sistermans, Erik A., Dalton, Ann, Meijers-Heijboer, Hanne, Pals, Gerard
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Catalysis; Collagen - chemistry; Comparative analysis; Cyclophilins - genetics; Cyclophilins - metabolism; Cyclophilins - physiology; Diseases of the osteoarticular system; DNA Mutational Analysis; Family Health; Female; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Humans; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical genetics; Medical sciences; Molecular and cellular biology; Mutation; Osteogenesis Imperfecta - genetics; Pregnancy; Procollagen-Proline Dioxygenase - metabolism; Proline - chemistry; Protein Structure, Tertiary; Proteins
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2009.09.001

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 α1 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 α1 chains of collagen type I.