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, α1(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 α1(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.
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Change history
26 June 2008
In the version of this article initially published, the nucleotide positions of the mutations in the LEPRE1 cDNA and genomic DNA sequence in Table 1, Supplementary Table 1 and Supplementary Figure 1 were incorrectly numbered relative to the first nucleotide of exon 1 rather than the first nucleotide of the LEPRE1 start codon. These errors have been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank the families of the probands for their commitment to and long-term support of our research. W.A.C. is a graduate student in the Molecular and Cell Biology Program of the University of Maryland. A. Galicka performed preliminary collagen cDNA sequencing and Q. Wang conducted prior collagen electrophoretic studies on probands 2 and 4. We thank the clinical teams that have provided care for the probands and their families, including L. Vera and M. France for proband 1, E. Carson, H. Stern, J. Larson and J. Fonda for proband 2, and T. Markello and L. Tosi for proband 3. D.R.E. acknowledges grant support from US National Institutes of Health AR37318 and HD 22657.
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W.A.C., W.C., A.M.B. were responsible for the design and execution of all experiments except for the differential scanning calorimetry (E.M. and N.V.K., under the guidance of S.L.) and mass spectrometry (M.A.W. and M.A.S., under the guidance of D.R.E.). K.N.R., C.J.T., D.I.B., C.K. and P.A.S. referred the probands to J.C.M. and contributed syndrome description and clinical insights. The manuscript was primarily written by J.C.M., with contributions from W.A.C. and critical revisions from W.C., A.M.B., D.R.E. and S.L. J.C.M. was responsible for overall study strategy and design, and clinical insight in selection of cases to be screened.
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Supplementary information
Supplementary Fig. 1
LEPRE1 mutations in severe recessive osteogenesis imperfecta. (PDF 143 kb)
Supplementary Fig. 2
Identification of leprecan in the extracellular matrix of murine bone. (PDF 42 kb)
Supplementary Table 1
PCR primers for mutation analysis and transcript structure determination. (PDF 24 kb)
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Cabral, W., Chang, W., Barnes, A. et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet 39, 359–365 (2007). https://doi.org/10.1038/ng1968
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DOI: https://doi.org/10.1038/ng1968
