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 13.9 and pQCT vBMD was 13.1; Patient 2 had L1-L4 DXA Z-score of 0.0 and pQCT vBMD of À1.8. 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 pCcollagen 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.

Genetic epidemiology, prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta

“…25 Seven individuals, from five families, harbored COL1A1 C-propeptide mutations. Two unrelated individuals had OI-EDS caused by mutations in COL1A1 (n = 1) and COL1A2 (n = 1).…”

“…25 Furthermore, in several cases parents were diagnosed via their children. This supports referral for genetic analysis of unclear bone fragility; however, cost of sequencing is still considerable in most clinical settings.…”

“…Exons were numbered as in NG_007400.1 (COL1A1) and NG_007405.1 (COL1A2). All described variants were entered into the OI variant databases [17][18][19] for COL1A1 (https://oi.gene.le.ac.uk/home.php?select_db = COL1A1) and COL1A2 (https://oi.gene.le.ac.uk/home.php?select_db = COL1A2), with patient IDs, AN_004901 to AN_005123 and database ID COL1A1_00265 (previously reported 25 ). Variants were defined as novel if not previously reported here.…”

Bone Material Properties in Osteogenesis Imperfecta

“…1). (10) (18) High bone mass in C-propeptide cleavage site defects (61) Caffey disease with defect at p.Arg1014Cys (111) …”

“…Type 1 collagen a2 chain Yes Mild-lethal OI (18) High bone mass in C-propeptide cleavage site defects (61) Collagen folding PPIB Cyclophilin B Yes Moderate-lethal OI (112) …”