Null mutations in CRTAP or P3H1, encoding cartilage-associated protein and prolyl 3-hydroxylase 1, cause the severe bone dysplasias, types VII and VIII osteogenesis imperfecta. Lack of either protein prevents formation of the ER prolyl 3-hydroxylation complex, which catalyzes 3Hyp modification of types I and II collagen and also acts as a collagen chaperone. To clarify the role of the A1 3Hyp substrate site in recessive bone dysplasia, we generated knock-in mice with an α1(I)P986A substitution that cannot be 3-hydroxylated. Mutant mice have normal survival, growth, femoral breaking strength and mean bone mineralization. However, the bone collagen HP/LP crosslink ratio is nearly doubled in mutant mice, while collagen fibril diameter and bone yield energy are decreased. Thus, 3-hydroxylation of the A1 site α1(I)P986 affects collagen crosslinking and structural organization, but its absence does not directly cause recessive bone dysplasia. Our study suggests that the functions of the modification complex as a collagen chaperone are thus distinct from its role as prolyl 3-hydroxylase.

CRTAP或P3H1 中的空突变编码软骨相关蛋白和脯氨酰 3-羟化酶 1，导致严重的骨发育不良，VII 型和 VIII 型成骨不全症。任何一种蛋白质的缺乏都会阻止 ER 脯氨酰 3-羟基化复合物的形成，该复合物催化 I 型和 II 型胶原蛋白的 3Hyp 修饰，并且还充当胶原蛋白伴侣。为了阐明 A1 3Hyp 底物位点在隐性骨发育不良中的作用，我们生成了具有不能 3-羟基化的 α1(I)P986A 取代的敲入小鼠。突变小鼠具有正常的存活、生长、股骨断裂强度和平均骨矿化。然而，骨胶原蛋白 HP/LP 交联比在突变小鼠中几乎翻了一番，而胶原纤维直径和骨产量能量降低。因此，A1 位点 α1(I)P986 的 3-羟基化影响胶原交联和结构组织，但它的缺失并不直接导致隐性骨发育不良。我们的研究表明，修饰复合物作为胶原蛋白伴侣的功能与其作为脯氨酰 3-羟化酶的作用不同。