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

Jingru Shi,Yongli Guo,Tieliu Shi,Muxue Tang,Xin Ni,Jinmeng Jia,Meng Ren

doi:10.3389/fphar.2019.01200

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.

Highlights

Osteogenesis imperfecta (OI) is a phenotypically and genetically heterogeneous group of bone disorders characterized by bone fragility and skeletal deformity, owing to the abnormality of type I collagen formed by two α1(I) chains and one α2(I) chain
dentinogenesis imperfecta (DI) had a strong relationship with vertebral anomalies, no significant difference was observed between two variation types in vertebral anomalies
OI is a rare disease with bone disorders characterized by bone fragility and skeletal deformity

Summary

Introduction

Osteogenesis imperfecta (OI) is a phenotypically and genetically heterogeneous group of bone disorders characterized by bone fragility and skeletal deformity, owing to the abnormality of type I collagen formed by two α1(I) chains (encoded by COL1A1 gene) and one α2(I) chain (encoded by COL1A2 gene). The first is missense mutation, mainly involving glycine replacement within the Gly-Xaa-Yaa repeat (the Gly-substitution missense), which results in the synthesis of collagen with abnormal structure (Lin et al, 2015). The second is a group of variations that include frameshift, nonsense, and splicing mutations, which mainly lead to the reduced amount of normal type I collagen. Previous studies have shown that the second variation group is often associated with milder phenotypes, while the Gly-substitution missense usually lead to more severe phenotypes (Rauch et al, 2010; Zhang et al, 2012). Considering the phenotypic specificity of the Gly-substitution missense, we would like to investigate more potentially pathogenic Gly-substitution mutations for OI mechanism exploration

Methods

Results

Conclusion