Genotype-Phenotype Association Analysis Reveals New Pathogenic Factors for Osteogenesis Imperfecta Disease
Genotype-Phenotype Association Analysis Reveals New Pathogenic Factors for Osteogenesis Imperfecta Disease
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基因型-表型关联分析揭示成骨不全病的新致病因素
DOI：
10.3389/fphar.2019.01200
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发表时间：
2019-10-15
影响因子：
5.6
通讯作者：
Shi, Tieliu
中科院分区：
文献类型：
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作者：
Shi, Jingru;Ren, Meng;Shi, Tieliu
成骨不全（OI）是一种遗传性罕见疾病，主要由I型胶原结构异常引起，以骨脆性增加和骨量减少为特征。成骨不全的临床表现主要包括多发性反复骨折、皮肤变薄、巩膜变蓝、听力下降、心血管和肺系统异常、三角脸、牙本质发育不全（DI）、辅助行走等。目前已鉴定出20个致病基因18个亚型，其中COL1A1和COL1A2的变异是OI的主要致病因子。然而，骨形成过程的复杂性表明存在与OI相关的潜在新致病基因。为了全面探讨OI的发病机制，我们对OI疾病的基因型和表型进行了关联分析，发现COL1A1和COL1A2的突变在OI疾病表型中占很大比例。我们根据从文献中收集的155例OI患者的变异类型对临床表型和基因型进行分类，关联研究显示，三种表型（骨畸形、DI、辅助行走）富集在两种变异类型（Gly取代错义和移码、无义和剪接变异组）中。我们还在基因COL1A1中鉴定了四种新的变异（c.G3290A（p.G1097D）、c.G3289C（p.G1097R）、c.G3289A（p.G1097S）、c.G3281A（p.G1094D）），在基因COL1A2中鉴定了两种新的变异（c.G2332T（p.G778C）、c.G2341T（p.G781C）），它们可能与疾病有关。此外，我们还通过整合蛋白质相互作用和途径富集分析，鉴定了几个新的潜在致病基因（ADAMTS2、COL5A2、COL8A1）。我们的研究为OI的基因型和表型之间的关联提供了新的见解，并为解剖疾病的潜在机制提供了新的信息。
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.