Genotype–Phenotype Association Analysis Reveals New Pathogenic Factors for Osteogenesis Imperfecta Disease

Abstract

Osteogenesis imperfecta (OI), mainly caused by structural abnormalities of type I collagen, is a hereditary rare disease characterized by increased bone fragility and reduced bone mass. Clinical manifestations of OI mostly include multiple repeated bone fractures, thin skin, blue sclera, hearing loss, cardiovascular and pulmonary system abnormalities, triangular face, dentinogenesis imperfecta (DI), and walking with assistance. Currently, 20 causative genes with 18 subtypes have been identified for OI, of them, variations in COL1A1 and COL1A2 have been demonstrated to be major causative factors to OI. However, the complexity of the bone formation process indicates that there are potential new pathogenic genes associated with OI. To comprehensively explore the underlying mechanism of OI, we conducted association analysis between genotypes and phenotypes of OI diseases and found that mutations in COL1A1 and COL1A2 contributed to a large proportion of the disease phenotypes. We categorized the clinical phenotypes and the genotypes based on the variation types for those 155 OI patients collected from literature, and association study revealed that three phenotypes (bone deformity, DI, walking with assistance) were enriched in two variation types (the Gly-substitution missense and groups of frameshift, nonsense, and splicing variations). We also identified four novel variations (c.G3290A (p.G1097D), c.G3289C (p.G1097R), c.G3289A (p.G1097S), c.G3281A (p.G1094D)) in gene COL1A1 and two novel variations (c.G2332T (p.G778C), c.G2341T (p.G781C)) in gene COL1A2, which could potentially contribute to the disease. In addition, we identified several new potential pathogenic genes (ADAMTS2, COL5A2, COL8A1) based on the integration of protein–protein interaction and pathway enrichment analysis. Our study provides new insights into the association between genotypes and phenotypes of OI and novel information for dissecting the underlying mechanism of the disease.

Whole Exome Sequencing Identifies a Novel COL1A1 Missense Mutation Causing Dentinogenesis Imperfecta Type I Without Skeletal Abnormalities

“…lead to the synthesis of a reduced amount of normal type I collagen; the other is structural defect including missense mutation, mainly involving glycine replacement within Gly-Xaa-Yaa repeat. In the collagen triple helix, the Gly-substitution missense will produce structural deformation of the triple helix, leading to destabilization of the helical structure, affecting the synthesis of collagen [17][18][19][20]. In our study, the singlebase substitution in a Gly codon leading to Ala substitutions, c.1463G>C (p.G488A) (Fig.…”

Case Report: A Novel COL1A1 Missense Mutation Associated With Dentineogenesis Imperfecta Type I

“…Type I collagen is the most abundant tooth matrix protein and is an ordered heterotrimer that is composed of two α1(I) chains and one α2(I) chain encoded by COL1A1 and COL1A2 genes, respectively (Brodsky and Persikov, 2005 ). Previous studies have shown that the missense substitution of glycine can cause the deformation of the triple helix structure of collagen, instability of the helical structure, and an abnormal synthesis of collagen (Brodsky and Persikov, 2005 ; Sun et al, 2015 ; Shi et al, 2019 ). Notably, the replacement of glycine seems to be linked to the degree of clinical severity of OI (Persikov et al, 2004 ; Qiu et al, 2018 ).…”

Current Insights into Collagen Type I

“…The assembly of the three α chains into the monomers of collagen trimeric is greatly influenced by C-propeptides [ 29 ]. Meanwhile, N-linked carbohydrates and intra-chain disulfide bonds stabilize the C-propeptide globular structure.…”