COL1A1/2 Pathogenic Variants and Phenotype Characteristics in Ukrainian Osteogenesis Imperfecta Patients

Abstract

Osteogenesis imperfecta (OI) is a hereditary bone disorder caused by defects of type I collagen. Although up to 90% of patients harbor pathogenic variants in the COL1A1/2 gene, which codes for collagen α1/2 chains, the spectrum of OI genotypes may differ between populations, and there is academic controversy around OI genotype-phenotype correlations. In the current study, 94 Ukrainian OI families were interviewed. Clinical and genealogical information was collected from patients in spoken form, and their phenotypes were described. To identify the spectrum of collagen I pathogenic variants, COL1A1/2 mutational analysis with Sanger sequencing was performed on the youngest affected individual of every family. Of the 143 patients investigated, 67 (46.85%) had type I OI, 24 (16.78%) had type III, 49 (34.27%) had type IV, and III (2.10%) had type V. The mean number of fractures suffered per patient per year was 1.32 ± 2.88 (type I 0.50 ± 0.43; type III 3.51 ± 6.18; type IV 1.44 ± 1.77; and type 5 0.77 ± 0.23). 87.23% of patients had skeletal deformations of different severity. Blue sclera, dentinogenesis imperfecta, and hearing loss were present in 87%, 55%, and 22% of patients, respectively. COL1A1/2 pathogenic variants were harbored by 60 patients (63.83%). 27 pathogenic variants are described herein for the first time. The majority of the pathogenic variants were located in the COL1A1 gene (76.19%). Half (49.21%) of the pathogenic variants were represented by structural variants. OI phenotype severity was highly correlated with type of collagen I defect. The current article presents an analysis of the clinical manifestations and COL1A1/2 mutational spectrum of 94 Ukrainian OI families with 27 novel COL1A1/2 pathogenic variants. It is hoped that this data and its analysis will contribute toward the increased understanding of the phenotype development and genetics of the disorder.

Collagen transport and related pathways in Osteogenesis Imperfecta

“…uk). A general trend supports an occurrence of a mild phenotype arising from less collagen production (nullallele) and a more severe phenotype as a result of structural collagen abnormalities from collagen defects or defects in collagen-modifying enzymes (Zhytnik et al 2019). Also, in certain cases, the severity of the phenotype can be explained by the effect of the mutation.…”

Histopathology of osteogenesis imperfecta bone. Supramolecular assessment of cells and matrices in the context of woven and lamellar bone formation using light, polarization and ultrastructural microscopy

“…While several generalized findings regarding the effects of types and positions of mutations have been made, the relation of molecular defects to clinical status is far from definitive. The mildest form of OI, nondeforming Sillence type I dominant, is generally caused by quantitative defects resulting from nonsense mutations leading to decreased production of normal type I collagen molecules by the haploinsufficiency effect; less protein produced but that produced is structurally normal ( Ben Amor et al, 2013 ; Lin et al, 2015 ; Zhytnik et al, 2019 ). Qualitative defects lead to an abnormal collagen molecule and are caused by mutations in each of the COL1A1 and COL1A2, post-translational and bone synthesis-modifying groups ( Marini et al, 2017 ; Forlino and Marini, 2016 ; Morello, 2018 ).…”

Identification of Potential Core Genes Associated With the Progression of Stomach Adenocarcinoma Using Bioinformatic Analysis

“…Omar Ret al, reported that COL1A2 affects cell migration of fibrosarcoma and chondrosarcoma by acting on TBX3 (Omar et al, 2019). Several studies have shown that COL1A1/2 plays a huge role in osteogenesis (Pollitt et al, 2006;Sato et al, 2016;Wang et al, 2019;Zhytnik et al, 2019). COL1A1 and COL1A2 have been shown to play an important prognostic role in STAD (Tamilzhalagan et al, 2017;Shi et al, 2019;Li J. et al, 2020).…”