PPIB Mutations Cause Severe Osteogenesis Imperfecta
PPIB Mutations Cause Severe Osteogenesis Imperfecta
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DOI：
10.1016/j.ajhg.2009.09.001
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发表时间：
2009-10-09
影响因子：
9.8
通讯作者：
Pals, Gerard
中科院分区：
文献类型：
--
作者：
van Dijk, Fleur S.;Nesbitt, Isabel M.;Pals, Gerard
据报道，常染色体隐性致死性或严重成骨不全症（OI）中存在软骨相关蛋白（CRTAP）或脯氨酸3-羟化酶1（P3H1）的缺乏。CRTAP， P3H1和亲环蛋白B （CyPB）形成细胞内胶原修饰复合物，在i型胶原α - 1链的986 （P986）位置3-羟化脯氨酸，这种3-脯氨酸羟化在CRTAP和P3H1缺乏的患者中减少。我们怀疑编码CyPB的PPIB基因突变也会导致胶原3-脯氨酸羟基化降低的成骨不全。据我们所知，我们提出了由PPIB基因突变引起的隐性OI的前两个家族。临床表型与OI沉默型II-B/III相一致，如COL1A1/2、CRTAP和LEPRE1突变。PPIB突变患者中3-羟基化P986残基的百分比与正常患者相比有所下降，但高于CRTAP和LEPRE1突变患者。这一结果和CyPB被证明独立于CRTAP和P3H1的事实，以及由于缺乏催化羟基化结构域的CRTAP和CyPB作为顺反异构酶的已知功能而导致的3-脯氨酸羟基化减少，表明隐性OI是由P3H1/CRTAP/CyPB复合物功能失调引起的，而不是由I型胶原α - 1链中单个脯氨酸残基缺乏3-脯氨酸羟基化引起的。
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 alpha 1 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 alpha 1 chains of collagen type I.