CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta

Dustin Baldridge, Ulrike Schwarze, Roy Morello, Jennifer Lennington, Terry K. Bertin, James M. Pace, Melanie G. Pepin, Maryann Weis, David R. Eyre, Jennifer Walsh, Deborah Lambert, Andrew Green, Haynes Robinson, Melonie Michelson, Gunnar Houge, Carl Lindman, Judith Martin, Jewell Ward, Emmanuelle Lemyre, John J. MitchellDeborah Krakow, David L. Rimoin, Daniel H. Cohn, Peter H. Byers, Brendan Lee

Research output: Contribution to journalArticlepeer-review

183 Scopus citations


Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Recently, dysregulation of hydroxylation of a single proline residue at position 986 of both the triple-helical domains of type I collagen α1(I) and type II collagen α1(II) chains has been implicated in the pathogenesis of recessive forms of OI. Two proteins, cartilage-associated protein (CRTAP) and prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene) form a complex that performs the hydroxylation and brings the prolyl cis-trans isomerase cyclophilin-B (CYPB) to the unfolded collagen. In our screen of 78 subjects diagnosed with OI type II or III, we identified three probands with mutations in CRTAP and 16 with mutations in LEPRE1. The latter group includes a mutation in patients from the Irish Traveller population, a genetically isolated community with increased incidence of OI. The clinical features resulting from CRTAP or LEPRE1 loss of function mutations were difficult to distinguish at birth. Infants in both groups had multiple fractures, decreased bone modeling (affecting especially the femurs), and extremely low bone mineral density. Interestingly, "popcorn" epiphyses may reflect underlying cartilaginous and bone dysplasia in this form of OI. These results expand the range of CRTAP/LEPRE1 mutations that result in recessive OI and emphasize the importance of distinguishing recurrence of severe OI of recessive inheritance from those that result from parental germline mosaicism for COL1A1 or COL1A2 mutations.

Original languageEnglish
Pages (from-to)1435-1442
Number of pages8
JournalHuman mutation
Issue number12
StatePublished - Dec 2008


  • COLIA1
  • COLIA2
  • LEPRE1
  • OI
  • Osteogenesis imperfecta
  • Prolyl 3-hydroxylation


Dive into the research topics of 'CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta'. Together they form a unique fingerprint.

Cite this