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Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation
  1. A Willaert1,
  2. F Malfait1,
  3. S Symoens1,
  4. K Gevaert2,3,
  5. H Kayserili4,
  6. A Megarbane5,
  7. G Mortier1,
  8. J G Leroy1,
  9. P J Coucke1,
  10. A De Paepe1
  1. 1
    Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium
  2. 2
    Department of Biochemistry, Ghent University, Ghent, Belgium
  3. 3
    Department of Medical Protein Research, VIB, Ghent, Belgium
  4. 4
    Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
  5. 5
    Medical Genetics Unit, Saint-Joseph University, Beirut, Lebanon
  1. Dr A De Paepe, Department of Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium; anne.depaepe{at}


Background: Recessive forms of osteogenesis imperfecta (OI) may be caused by mutations in LEPRE1, encoding prolyl 3-hydroxylase-1 (P3H1) or in CRTAP, encoding cartilage associated protein. These proteins constitute together with cyclophilin B (CyPB) the prolyl 3-hydroxylation complex that hydroxylates the Pro986 residue in both the type I and type II collagen α1-chains.

Methods: We screened LEPRE1, CRTAP and PPIB (encoding CyPB) in a European/Middle Eastern cohort of 20 lethal/severe OI patients without a type I collagen mutation.

Results: Four novel homozygous and compound heterozygous mutations were identified in LEPRE1 in four probands. Two probands survived the neonatal period, including one patient who is the eldest reported patient (177/12 years) so far with P3H1 deficiency. At birth, clinical and radiologic features were hardly distinguishable from those in patients with autosomal dominant (AD) severe/lethal OI. Follow-up data reveal that the longer lived patients develop a severe osteochondrodysplasia that overlaps with, but has some distinctive features from, AD OI. A new splice site mutation was identified in two of the four probands, affecting only one of three LEPRE1 mRNA splice forms, detected in this study. The affected splice form encodes a 736 amino acid (AA) protein with a “KDEL” endoplasmic reticulum retention signal. While western blotting and immunocytochemical analysis of fibroblast cultures revealed absence of this P3H1 protein, mass spectrometry and SDS-urea-PAGE data showed severe reduction of α1(I)Pro986 3-hydroxylation and overmodification of type I (pro)collagen chains in skin fibroblasts of the patients.

Conclusion: These findings suggest that the 3-hydroxylation function of P3H1 is restricted to the 736AA splice form.

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  • Funding: This study was supported by the Fund for Scientific Research, Flanders (Belgium) (grant G.0171.05) and Ghent University (grants 12051203 and 01M01108)

  • Competing interests: None declared.

  • Ethics approval: Approval for this study was provided by the local ethics committee (Ethics committee, Ghent University Hospital, Ghent, Belgium).

  • Patient consent: Obtained.