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
Department of Clinical Genetics, VU University Medical Centre, De Boelelaan 1117, P.O. box 7057, 1007 MB Amsterdam, The Netherlands.
Am J Hum Genet. 2009 Oct;85(4):521-7. doi: 10.1016/j.ajhg.2009.09.001. Epub 2009 Sep 24.
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.
据报道，常染色体隐性致死性或严重成骨不全（OI）患者存在软骨相关蛋白（CRTAP）或脯氨酰3-羟化酶1（P3H1）缺乏。CRTAP、P3H1和亲环蛋白B（CyPB）形成一种细胞内胶原修饰复合物，该复合物可将I型胶原α1链中第986位（P986）的脯氨酸进行3-羟化。CRTAP和P3H1缺乏的患者中这种3-脯氨酰羟化作用减弱。有人怀疑，编码CyPB的PPIB基因突变也会导致OI且胶原3-脯氨酰羟化作用减弱。据我们所知，我们首次报道了两个由PPIB基因突变引起的隐性OI家系。临床表型与COL1A1/2、CRTAP和LEPRE1突变所见的OI Sillence II-B/III型相符。与正常情况相比，PPIB基因突变患者中3-羟化P986残基的百分比降低，但高于CRTAP和LEPRE1基因突变患者。这一结果以及CyPB可独立于CRTAP和P3H1被检测到这一事实，再加上报道称由于缺乏催化羟化结构域的CRTAP缺乏导致3-脯氨酰羟化作用降低，以及已知CyPB作为顺反异构酶的功能，表明隐性OI是由功能失调的P3H1/CRTAP/CyPB复合物引起的，而不是由I型胶原α1链中单个脯氨酸残基的3-脯氨酰羟化作用缺乏引起的。
