title: COL1 C-propeptide cleavage site mutations cause high bone mass osteogenesis imperfecta.
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.
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Lindahl
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Barnes
authors.forename: Nadja
authors.initials: N
authors.lastname: Fratzl-Zelman
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
authors.forename: Theresa E
authors.initials: TE
authors.lastname: Hefferan
authors.forename: Elena
authors.initials: E
authors.lastname: Makareeva
authors.forename: Marina
authors.initials: M
authors.lastname: Brusel
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Yaszemski
authors.forename: Carl-Johan
authors.initials: CJ
authors.lastname: Rubin
authors.forename: Andreas
authors.initials: A
authors.lastname: Kindmark
authors.forename: Paul
authors.initials: P
authors.lastname: Roschger
authors.forename: Klaus
authors.initials: K
authors.lastname: Klaushofer
authors.forename: William H
authors.initials: WH
authors.lastname: McAlister
authors.forename: Steven
authors.initials: S
authors.lastname: Mumm
authors.forename: Sergey
authors.initials: S
authors.lastname: Leikin
authors.forename: Efrat
authors.initials: E
authors.lastname: Kessler
authors.forename: Adele L
authors.initials: AL
authors.lastname: Boskey
authors.forename: Osten
authors.initials: O
authors.lastname: Ljunggren
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D015519:Bone Density / Q000235:genetics; D001857:Bone Matrix; D001842:Bone and Bones / Q000002:abnormalities* / Q000473:pathology*; D002113:Calcification, Physiologic / Q000235:genetics; D002648:Child; D024042:Collagen Type I / Q000235:genetics* / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000473:pathology*; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011347:Procollagen / Q000235:genetics* / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D010446:Peptide Fragments; D011347:Procollagen; C042813:procollagen type I carboxy terminal peptide