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Type I Procollagen C‐Propeptide Defects: Study of Genotype–Phenotype Correlation and Predictive Role of Crystal Structure
Author(s) -
Symoens Sofie,
Hulmes David J.S.,
Bourhis JeanMarie,
Coucke Paul J.,
De Paepe Anne,
Malfait Fransiska
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22677
Subject(s) - procollagen peptidase , protein precursor , phenotype , missense mutation , biology , genetics , exon , genotype , frameshift mutation , nonsense mediated decay , nonsense , nonsense mutation , microbiology and biotechnology , gene , rna splicing , rna
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 m RNA 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 . P roα1(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.