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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. Andy Willaert (andy.willaert{at}ugent.be)
  1. Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium
    1. Fransiska Malfait
    1. Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium
      1. Sofie Symoens
      1. Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium
        1. Kris Gevaert
        1. Depart. of Biochemistry, Ghent University, Ghent and Depart. of Medical Protein Research, VIB Ghent, Belgium
          1. Hulya Kayserili
          1. Medical Genetics Department, Instanbul Medical Faculty, Instanbul University, Istanbul, Turkey
            1. Andre Megarbane
            1. Medical Genetics Unit, Saint-Joseph University, Beirut, Lebanon
              1. Geert Mortier
              1. Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium
                1. Jules Leroy
                1. Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium
                  1. Paul Coucke
                  1. Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium
                    1. Anne De Paepe (anne.depaepe{at}ugent.be)
                    1. Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium

                      Abstract

                      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. 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. Four novel homozygous and compound heterozygous mutations were identified in LEPRE1 in 4 probands. Two probands survived the neonatal period, including one patient, who is the eldest reported patient (177/12 y) 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. These findings suggest that the 3-hydroxylation function of P3H1 is restricted to the 736AA splice form.

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