Letter abstract

Nature Genetics 39, 359 - 365 (2007)
Published online: 4 February 2007 | Corrected online: 26 June 2008 | doi:10.1038/ng1968



There is a Corrigendum (July 2008) associated with this Letter.

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

Wayne A Cabral1,8, Weizhong Chang1,8, Aileen M Barnes1, MaryAnn Weis2, Melissa A Scott2, Sergey Leikin3, Elena Makareeva3, Natalia V Kuznetsova3, Kenneth N Rosenbaum4, Cynthia J Tifft4, Dorothy I Bulas5, Chahira Kozma6, Peter A Smith7, David R Eyre2 & Joan C Marini1

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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.

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  1. Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
  2. Orthopaedic Research Laboratories, University of Washington, Seattle, Washington 98195, USA.
  3. Section on Physical Biochemistry, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
  4. Department of Genetics, Children's National Medical Center, Washington, DC 20010, USA.
  5. Department of Diagnostic Imaging and Radiology, Children's National Medical Center, Washington, DC 20010, USA.
  6. Department of Pediatrics, Georgetown University Hospital, Washington, DC 20007, USA.
  7. Shriners' Hospital for Children, Chicago, Illinois 60707, USA.
  8. These authors contributed equally to this work.

Correspondence to: Joan C Marini1 e-mail: oidoc@helix.nih.gov

* 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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