Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta.
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.
Cabral
Wayne A
WA
Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Chang
Weizhong
W
Barnes
Aileen M
AM
Weis
MaryAnn
M
Scott
Melissa A
MA
Leikin
Sergey
S
Makareeva
Elena
E
Kuznetsova
Natalia V
NV
Rosenbaum
Kenneth N
KN
Tifft
Cynthia J
CJ
Bulas
Dorothy I
DI
Kozma
Chahira
C
Smith
Peter A
PA
Eyre
David R
DR
Marini
Joan C
JC
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
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