COL1 C-propeptide cleavage site mutations cause high bone mass osteogenesis imperfecta

Katarina Lindahl, Aileen M. Barnes, Nadja Fratzl-Zelman, Michael P. Whyte, Theresa E. Hefferan, Elena Makareeva, Marina Brusel, Michael J. Yaszemski, Carl Johan Rubin, Andreas Kindmark, Paul Roschger, Klaus Klaushofer, William H. Mcalister, Steven Mumm, Sergey Leikin, Efrat Kessler, Adele L. Boskey, Östen Ljunggren, Joan C. Marini*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

115 Scopus citations


Osteogenesis imperfecta (OI) is most often caused by mutations in the type I procollagen genes (COL1A1/COL1A2). We identified two children with substitutions in the type I procollagen C-propeptide cleavage site, which disrupt a unique processing step in collagen maturation and define a novel phenotype within OI. The patients have mild OI caused by mutations in COL1A1 (Patient 1: p.Asp1219Asn) or COL1A2 (Patient 2: p.Ala1119Thr), respectively. Patient 1 L1-L4 DXA Z-score was +3.9 and pQCT vBMD was+3.1; Patient 2 had L1-L4 DXA Z-score of 0.0 and pQCT vBMD of -1.8. Patient BMD contrasts with radiographic osteopenia and histomorphometry without osteosclerosis. Mutant procollagen processing is impaired in pericellular and in vitro assays. Patient dermal collagen fibrils have irregular borders. Incorporation of pC-collagen into matrix leads to increased bone mineralization. FTIR imaging confirms elevated mineral/matrix ratios in both patients, along with increased collagen maturation in trabecular bone, compared to normal or OI controls. Bone mineralization density distribution revealed a marked shift toward increased mineralization density for both patients. Patient 1 has areas of higher and lower bone mineralization than controls; Patient 2's bone matrix has a mineral content exceeding even classical OI bone. These patients define a new phenotype of high BMD OI and demonstrate that procollagen C-propeptide cleavage is crucial to normal bone mineralization.

Original languageEnglish
Pages (from-to)598-609
Number of pages12
JournalHuman Mutation
Issue number6
StatePublished - Jun 2011


FundersFunder number
National Institute of Child Health and Human DevelopmentZIAHD000256


    • C-propeptide
    • C-proteinase
    • Collagen
    • High bone mass
    • Mineralization
    • Osteogenesis imperfecta


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