Genotype-Phenotype Association Analysis Reveals New Pathogenic Factors for Osteogenesis Imperfecta Disease (vol 10, 1200, 2019)

“To validate the pathogenicity of the candidate variations in COL1A1, we checked the specificity of their locations (positions of the four candidate mutations: 1094 and 1097). Evidence from the protein families database (Pfam) (El-Gebali et al., 2019) demonstrate that the locations of all four variations belong to the collagen triple helix region (PF01391: Collagen triple helix repeat (1079-1137)). Structurally, different abnormalities in the collagen helix are associated with the identity of the residue replacing Gly (Bryan et al., 2011; Qiu et al., 2018), which also influence the severity of OI patients (residues replacing Gly of four candidate mutations: Asp, Arg, and Ser). Through the statistical analysis on the location of Glysubstitution mutations in a large number of OI patients, Beck et al. found that all Gly!Asp in the a1(l) chain led to OI type II (perinatal lethat form) (Beck et al., 2000). In addition, the study of the impact of various Gly replacements discovered that the three replaced form (Gly!Arg, Gly!Ser, and Gly!Cys) had a stronger association with OI lethality than the other replaced forms (Beck et al., 2000). In all, these conclusions indicate that the four candidate mutations of COL1A1 we identified are highly likely to cause lethal OI phenotypes. Copyright © 2020 Shi, Ren, Jia, Tang, Guo, Ni and Shi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.