Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta
Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta
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DOI：
10.1038/ng1968
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发表时间：
2007-03-01
期刊：
影响因子：
30.8
通讯作者：
Marini, Joan C.
中科院分区：
文献类型：
--
作者：
Cabral, Wayne A.;Chang, Weizhong;Marini, Joan C.
长期以来，人们一直怀疑存在一种并非由I型胶原蛋白突变引起的隐性严重成骨不全症。据报道，人类CRTAP（软骨相关蛋白）突变可导致隐性骨病。CRTAP与亲环蛋白B和脯氨酰3 - 羟化酶1形成复合物，脯氨酰3 - 羟化酶1由LEPRE1编码，可羟化I型胶原蛋白α1(I) Pro986的一个残基。我们介绍了首批5例由LEPRE1无效等位基因导致的新型隐性骨病病例；其表型与致死性/严重成骨不全症有重叠，但具有独特特征。此外，在5例中有4例出现了一个来自西非的突变等位基因（在非裔美国人中也有发现）。所有先证者的LEPRE1突变都导致了提前终止密码子以及极少量的mRNA和蛋白质。先证者的胶原蛋白中α1(I) Pro986的3 - 羟化程度极低，但沿着胶原蛋白螺旋的赖氨酰羟化和糖基化过度。先证者的胶原蛋白分泌有中度延迟，但总胶原蛋白分泌量增加。因此，脯氨酰3 - 羟化酶1对骨骼发育和胶原蛋白螺旋形成至关重要。
A recessive form of severe osteogenesis imperfecta that is not caused by mutations in type I collagen has long been suspected. Mutations in human CRTAP (cartilage-associated protein) causing recessive bone disease have been reported. CRTAP forms a complex with cyclophilin B and prolyl 3-hydroxylase 1, which is encoded by LEPRE1 and hydroxylates one residue in type I collagen, alpha 1(I) Pro986. We present the first five cases of a new recessive bone disorder resulting from null LEPRE1 alleles; its phenotype overlaps with lethal/severe osteogenesis imperfecta but has distinctive features. Furthermore, a mutant allele from West Africa, also found in African Americans, occurs in four of five cases. All proband LEPRE1 mutations led to premature termination codons and minimal mRNA and protein. Proband collagen had minimal 3-hydroxylation of alpha 1(I) Pro986 but excess lysyl hydroxylation and glycosylation along the collagen helix. Proband collagen secretion was moderately delayed, but total collagen secretion was increased. Prolyl 3-hydroxylase 1 is therefore crucial for bone development and collagen helix formation.