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

• Published in: Human mutation Vol. 32; no. 6; pp. 598 - 609
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.06.2011; John Wiley & Sons, Inc
• Subjects: Adolescent; Amino Acid Sequence; Animals; Bone (trabecular); Bone and Bones - abnormalities; Bone and Bones - pathology; Bone Density - genetics; Bone histomorphometry; Bone imaging; Bone mass; Bone Matrix; Bone mineral density; C-propeptide; C-proteinase; Calcification, Physiologic - genetics; Child; Children; Collagen; Collagen (type I); Collagen Type I - genetics; Collagen Type I - metabolism; Collagen Type I, alpha 1 Chain; Computed tomography; Dual energy X-ray absorptiometry; Female; Fibrils; high bone mass; Humans; Male; MEDICIN; MEDICINE; Mice; Mineralization; Molecular Sequence Data; Mutation; Osteogenesis imperfecta; Osteogenesis Imperfecta - genetics; Osteogenesis Imperfecta - pathology; Osteopenia; Osteosclerosis; Peptide Fragments - genetics; Peptide Fragments - metabolism; Phenotype; procollagen; Procollagen - genetics; Procollagen - metabolism; Skin
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.21475

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. Hum Mutat 32:1–12, 2011. © 2011 Wiley‐Liss, Inc.