title: Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta.
abstract: 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, alpha1(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 alpha1(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.
authors.affiliation: Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Cabral
authors.forename: Weizhong
authors.initials: W
authors.lastname: Chang
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Barnes
authors.forename: MaryAnn
authors.initials: M
authors.lastname: Weis
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Scott
authors.forename: Sergey
authors.initials: S
authors.lastname: Leikin
authors.forename: Elena
authors.initials: E
authors.lastname: Makareeva
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Kuznetsova
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Rosenbaum
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Tifft
authors.forename: Dorothy I
authors.initials: DI
authors.lastname: Bulas
authors.forename: Chahira
authors.initials: C
authors.lastname: Kozma
authors.forename: Peter A
authors.initials: PA
authors.lastname: Smith
authors.forename: David R
authors.initials: DR
authors.lastname: Eyre
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
mesh_terms: D001851:Bone Diseases, Metabolic / Q000235:genetics* / Q000473:pathology; D024042:Collagen Type I / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency / Q000235:genetics; D064828:Prolyl Hydroxylases; D011509:Proteoglycans / Q000172:deficiency* / Q000235:genetics*; D011859:Radiography; D013997:Time Factors; D016216:Ultrasonography, Prenatal
chemical_list: D024042:Collagen Type I; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D064828:Prolyl Hydroxylases; D011393:Procollagen-Proline Dioxygenase; C485657:P3H1 protein, human; C030606:proline, 2-oxoglutarate 3-dioxygenase