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

Research output: Contribution to journalArticle

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Abstract

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 (US)
Pages (from-to)598-609
Number of pages12
JournalHuman Mutation
Volume32
Issue number6
DOIs
StatePublished - Jun 2011

Fingerprint

Osteogenesis Imperfecta
Bone and Bones
Mutation
Physiologic Calcification
Collagen
Procollagen
Collagen Type I
Minerals
Osteosclerosis
Phenotype
Bone Matrix
Metabolic Bone Diseases
Fourier Transform Infrared Spectroscopy
Bone Density

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Lindahl, K., Barnes, A. M., Fratzl-Zelman, N., Whyte, M. P., Hefferan, T. E., Makareeva, E., ... Marini, J. C. (2011). COL1 C-propeptide cleavage site mutations cause high bone mass osteogenesis imperfecta. Human Mutation, 32(6), 598-609. https://doi.org/10.1002/humu.21475

COL1 C-propeptide cleavage site mutations cause high bone mass osteogenesis imperfecta. / Lindahl, Katarina; Barnes, Aileen M.; Fratzl-Zelman, Nadja; Whyte, Michael P.; Hefferan, Theresa E.; Makareeva, Elena; Brusel, Marina; Yaszemski, Michael J; Rubin, Carl Johan; Kindmark, Andreas; Roschger, Paul; Klaushofer, Klaus; Mcalister, William H.; Mumm, Steven; Leikin, Sergey; Kessler, Efrat; Boskey, Adele L.; Ljunggren, Östen; Marini, Joan C.

In: Human Mutation, Vol. 32, No. 6, 06.2011, p. 598-609.

Research output: Contribution to journalArticle

Lindahl, K, Barnes, AM, Fratzl-Zelman, N, Whyte, MP, Hefferan, TE, Makareeva, E, Brusel, M, Yaszemski, MJ, Rubin, CJ, Kindmark, A, Roschger, P, Klaushofer, K, Mcalister, WH, Mumm, S, Leikin, S, Kessler, E, Boskey, AL, Ljunggren, Ö & Marini, JC 2011, 'COL1 C-propeptide cleavage site mutations cause high bone mass osteogenesis imperfecta', Human Mutation, vol. 32, no. 6, pp. 598-609. https://doi.org/10.1002/humu.21475
Lindahl K, Barnes AM, Fratzl-Zelman N, Whyte MP, Hefferan TE, Makareeva E et al. COL1 C-propeptide cleavage site mutations cause high bone mass osteogenesis imperfecta. Human Mutation. 2011 Jun;32(6):598-609. https://doi.org/10.1002/humu.21475
Lindahl, Katarina ; Barnes, Aileen M. ; Fratzl-Zelman, Nadja ; Whyte, Michael P. ; Hefferan, Theresa E. ; Makareeva, Elena ; Brusel, Marina ; Yaszemski, Michael J ; Rubin, Carl Johan ; Kindmark, Andreas ; Roschger, Paul ; Klaushofer, Klaus ; Mcalister, William H. ; Mumm, Steven ; Leikin, Sergey ; Kessler, Efrat ; Boskey, Adele L. ; Ljunggren, Östen ; Marini, Joan C. / COL1 C-propeptide cleavage site mutations cause high bone mass osteogenesis imperfecta. In: Human Mutation. 2011 ; Vol. 32, No. 6. pp. 598-609.
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