title: Type I procollagen C-propeptide defects: study of genotype-phenotype correlation and predictive role of crystal structure.
abstract: The type I procollagen carboxyterminal(C-)propeptides are crucial in directing correct assembly of the procollagen heterotrimers. Defects in these domains have anecdotally been reported in patients with Osteogenesis Imperfecta (OI) and few genotype-phenotype correlations have been described. To gain insight in the functional consequences of C-propeptide defects, we performed a systematic review of clinical, molecular, and biochemical findings in all patients in whom we identified a type I procollagen C-propeptide defect, and compared this with literature data. We report 30 unique type I procollagen C-propeptide variants, 24 of which are novel. The outcome of COL1A1 nonsense and frameshift variants depends on the location of the premature termination codon. Those located prior to 50-55 nucleotides upstream of the most 3' exon-exon junction lead to nonsense-mediated mRNA decay (NMD) and cause mild OI. Those located beyond this boundary escape NMD, generally lead to production of stable, overmodified procollagen chains, which may partly be retained intracellularly, and are usually associated with severe-to-lethal OI. Proα1(I)-C-propeptide defects that permit chain association result in more severe phenotypes than those inhibiting chain association. We demonstrate that the crystal structure of the proα1(III)-C-propeptide is a reliable tool to predict phenotypic severity for most COL1A1-C-propeptide missense variants, whereas for COL1A2-C-propeptide variants, the phenotypic outcome is milder than predicted.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000, Ghent, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Symoens
authors.forename: David J S
authors.initials: DJ
authors.lastname: Hulmes
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Bourhis
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coucke
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D024042:Collagen Type I / Q000737:chemistry / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D005091:Exons; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010013:Osteogenesis Imperfecta / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D010641:Phenotype; D011347:Procollagen; D011487:Protein Conformation; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D010446:Peptide Fragments; D011347:Procollagen
keywords: C-propeptide; COL1A1, COL1A2; genotype-phenotype; osteogenesis imperfecta; type I procollagen; unfolded protein response