Cabral WA, Chang W, Barnes AM, et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta

University of Washington Seattle, Seattle, Washington, United States
Nature Genetics (Impact Factor: 29.35). 04/2007; 39(3):359-65. DOI: 10.1038/ng1968
Source: PubMed


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.

Download full-text


Available from: Dorothy I Bulas,
  • Source
    • "Dominant mutations in IFITM5 can also cause OI, but the prevalence of this mutation is low [Cho et al., 2012; Semler et al., 2012]. Rare recessive genes have been reported to cause OI including CRTAP [Barnes et al., 2006], LEPRE1 [Cabral et al., 2007], FKBP10 [Alanay et al., 2010], PLOD2 [Puig-Hervas et al., 2012], PPIB [van Dijk et al., 2009], SERPINF1 [Becker et al., 2011], SER- PINH1 [Christiansen et al., 2010], SP7 [Lapunzina et al., 2010], TMEM38B [Shaheen et al., 2012], WNT1 [Fahiminiya et al., 2013], CREB3L1 [Symoens et al., 2013], and BMP1 [Martinez-Glez et al., 2012]. Type I collagen is assembled in the endoplasmic reticulum by the association of two proα1(I) collagen chains and one proα2(I) collagen chain into a triple helix. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal dominant inheritance; but, many autosomal recessive genes have been reported. We applied whole exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypo-functional nature of the two variants was demonstrated in a zebrafish assay.This article is protected by copyright. All rights reserved
    Human Mutation 11/2014; 36(2). DOI:10.1002/humu.22731 · 5.14 Impact Factor
  • Source
    • "Footnote. OI may also be classified into types V (Glorieux et al. [17]), VI (Glorieux et al. [18]), VII (Ward et al. [19]), and VIII (Cabral et al. [20]) based on clinical and bone histological parameters. these features [2]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteogenesis imperfecta (OI) is a rare hereditary condition caused by changes in collagen metabolism. It is classified into four types according to clinical, genetic, and radiological criteria. Clinically, bone fragility, short stature, blue sclerae, and locomotion difficulties may be observed in this disease. OI is often associated to severe dental problems, such as dentinogenesis imperfecta (DI) and malocclusions. Radiographically, affected teeth may have crowns with bulbous appearance, accentuated constriction in the cementoenamel junction, narrowed roots, large root canals due to defective dentin formation, and taurodontism (enlarged pulp chambers). There is no definitive cure, but bisphosphonate therapy is reported to improve bone quality; however, there is a potential risk of bisphosphonate-related osteonecrosis of the jaw. In this study we report a case of OI in a male pediatric patient with no family history of OI who was receiving ongoing treatment with intravenous perfusion of bisphosphonate and who required dental surgery. In addition, we discussed the clinical and imaging findings and briefly reviewed the literature.
    08/2014; 2014:384292. DOI:10.1155/2014/384292
  • Source
    • "Albeit uncommon, dominant transmission can also be caused by mutations in IFITM5 [Cho et al., 2012; Semler et al., 2012]. Autosomal recessive inheritance is seen in rare patients with OI (AR-OI) with mutations identified in CRTAP [Morello et al., 2006], LEPRE1 [Cabral et al., 2007], PPIB [van Dijk et al., 2009], SERPINH1 [Christiansen et al., 2010], FKBP10 [Alanay et al., 2010], SP7 [Lapunzina et al., 2010], SERPINF1 [Becker et al., 2011], BMP1 [Asharani et al., 2012; Martinez-Glez et al., 2012], PLOD2 [van der Slot et al., 2003; Puig-Hervas et al., 2012], TMEM38B [Shaheen et al., 2012], or WNT1 [Fahiminiya et al., 2013; Keupp et al., 2013; Laine et al., 2013; Pyott et al., 2013]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteogenesis imperfecta is a genetic condition characterized by bone fragility and recurrent fractures, which in the large majority of patients are caused by defects in the production of type I collagen. Mutations in the gene encoding bone morphogenetic protein 1 (BMP1, also known as procollagen C-endopeptidase) have been associated with osteogenesis imperfecta in two sib pairs. In this report, we describe an additional patient with osteogenesis imperfecta with normal bone density and a recurrent, homozygous c.34G>C mutation in BMP1. Western blot analysis of dermal fibroblasts from this patient showed decreased protein levels of the two alternatively spliced products of BMP1 and abnormal cleavage of the C-terminal propeptide of type I procollagen. In addition, fluorescence and electron microscopy showed impaired assembly of type I collagen fibrils in the extracellular matrix of cultured fibroblasts derived from two patients: the patient described here and a previously reported patient with a homozygous BMP1 c.747C>G mutation. We conclude that BMP1 is essential for human type I collagen fibrilogenesis. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 05/2014; 164(5). DOI:10.1002/ajmg.a.36427 · 2.16 Impact Factor
Show more