Article

Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta.

Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature Genetics (Impact Factor: 29.65). 04/2007; 39(3):359-65. DOI: 10.1038/ng1968
Source: PubMed

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.

0 Bookmarks
 · 
107 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone is a composite material that resembles reinforced concrete. The collagen matrix plays the role of reinforcement, whereas hydroxyapatite crystals are cementing material. Collagen fibers are responsible for the tensile strength of bones and prevent fractures from extending; the mineral phase is able to withstand compaction loads. A right balance of these two parts synergistically provides the required stiffness for bone. Collagen abnormalities, such as reduced amount, disturbed composition, defects in structure and/or supramolecular organization as well as insufficient or defective mineralization, lead to osteogenesis imperfecta (OI), also known as brittle bone disease. Until recently, mutations in the type I collagen genes COL1A1 and COL1A2 were the only known causes of the disease, which cover about 90 % of diagnosed OI. Within the last decade, we have witnessed a burst in the identification of new OI mutations in other genes. Here we summarize our knowledge of these mutations and their impact on bone quality.
    Current Genetic Medicine Reports. 12/2013; 1(4):239-246.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The present study evaluates a fetal skeleton (B532) from the Romano-Byzantine period Kellis 2 cemetery (circa A.D. 50–A.D. 450), in the Dakhleh Oasis, Egypt. This skeleton displays abnormal skeletal characteristics consisting of severe bowing of the long bones. Differential diagnoses using macroscopic and radiographic analyses indicate that this individual's pathological condition was caused by osteogenesis imperfecta (IO), possibly Type IIB/III, or Type IV OI, corroborating with characteristics reported in the clinical literature. Due to the severe bowing of the long bones, traditional aging methods could not be used for this individual. Baysian estimates of age indicate this individual was a fetus of approximately 38 weeks gestation. Although this condition has been diagnosed previously in the archeological literature, this burial represents the youngest aged example of osteogenesis imperfecta reported to date.
    International Journal of Paleopathology. 12/2011; 1(3-4):188-199.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteogenesis Imperfecta (OI) is a genetic disorder that results in low bone mineral density and brittle bones. Most cases result from dominant mutations in the type I procollagen genes, but mutations in a growing number of genes have been identified that produce autosomal recessive forms of the disease. Among these include mutations in the genes SERPINH1 and FKBP10 which encode the type I procollagen chaperones HSP47 and FKBP65, respectively, and predominantly produce a moderately severe form of OI. Little is known about the biochemical consequences of the mutations and how they produce OI. We have identified a new OI mutation in SERPINH1 that results in destabilization and mislocalization of HSP47, and secondarily has similar effects on FKBP65. We found evidence that HSP47 and FKBP65 act cooperatively during posttranslational maturation of type I procollagen and that FKBP65 and HSP47, but fail to properly interact in mutant HSP47 cells. These results thus reveal a common cellular pathway in cases of OI caused by HSP47 and FKBP65 deficiency. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 12/2014; · 6.68 Impact Factor

Full-text (2 Sources)

Download
185 Downloads
Available from
Jun 3, 2014