Homozygosity for a Missense Mutation in SERPINH1, which Encodes the Collagen Chaperone Protein HSP47, Results in Severe Recessive Osteogenesis Imperfecta
Homozygosity for a Missense Mutation in SERPINH1, which Encodes the Collagen Chaperone Protein HSP47, Results in Severe Recessive Osteogenesis Imperfecta
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DOI：
10.1016/j.ajhg.2010.01.034
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发表时间：
2010-03-12
影响因子：
9.8
通讯作者：
Byers, Peter H.
中科院分区：
文献类型：
--
作者：
Christiansen, Helena E.;Schwarze, Ulrike;Byers, Peter H.
成骨不全（OI）的特征是骨脆性和骨折，可能伴有骨畸形、牙本质不全、身材矮小和寿命缩短。约90%的O 1患者在I型胶原基因COL 1A 1和COL 1A 2中存在显性突变。最近已经鉴定出由胶原修饰酶和伴侣蛋白CRTAP、LEPRE 1、PPIB和FKBP 10突变引起的隐性形式的OI。我们已经鉴定了SERPINH 1中的常染色体隐性错义突变（c.233T>C，pLeu 78 Pro），其编码胶原蛋白伴侣样蛋白HSP 47，导致严重的01表型。该突变导致内质网驻留HSP 47通过蛋白酶体降解。1型前胶原积聚在来自受影响个体的成纤维细胞的高尔基体中，并且分泌的I型前胶原的群体是蛋白酶敏感的。这些研究结果表明，HSP 47监测在ER/顺式高尔基体边界的I型前胶原的三螺旋的完整性，当不存在时，从ER到高尔基体的转运速率增加，螺旋结构受损。pro α 1（1）链三螺旋结构域986位脯氨酰残基的正常3-羟基化使HSP 47的作用位于参与脯氨酰3-羟基化的CRTAP/P3 H1/CyPB复合物下游。SERPINH 1中这种突变的鉴定可以进一步了解胶原蛋白生物合成途径的关键步骤和OI的分子发病机制。
Osteogenesis imperfecta (OI) is characterized by bone fragility and fractures that may be accompanied by bone deformity, dentinogenesis imperfecta, short stature, and shortened life span. About 90% of individuals with 01 have dominant mutations in the type I collagen genes COL1A1 and COL1A2. Recessive forms of OI resulting from Mutations in collagen-modifying enzymes and chaperones CRTAP, LEPRE1, PPIB, and FKBP10 have recently been identified. We have identified an autosomal-recessive missense mutation (c.233T>C, pLeu78Pro) in SERPINH1, which encodes the collagen chaperone-like protein HSP47, that leads to a severe 01 phenotype. The mutation results in degradation of the endoplasmic reticulum resident HSP47 via the proteasome. Type 1 procollagen accumulates in the Golgi of fibroblasts from the affected individual and a population of the secreted type I procollagen is protease sensitive. These findings suggest that HSP47 monitors the integrity of the triple helix of type I procollagen at the ER/cis-Golgi boundary and, when absent, the rate of transit from the ER to the Golgi is increased and helical structure is compromised. The normal 3-hydroxylation of the prolyl residue at position 986 of the triple helical domain of pro alpha 1(1) chains places the role of HSP47 downstream from the CRTAP/P3H1/CyPB complex that is involved in prolyl 3-hydroxylation. Identification of this mutation in SERPINH1 gives further insight into critical steps of the collagen biosynthetic pathway and the molecular pathogenesis of OI.