In vitro and in silico analysis of a E559K mutation on cartilage oligomeric matrix protein

IF 1.5 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2022-01-01 DOI:10.1016/j.mrfmmm.2022.111774

Jiahui Qiu , Jichun Tan

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Abstract

Pseudoachondroplasia (PSACH) is known as an autosomal dominant disorder associated with mutations in the gene of cartilage oligomeric matrix protein (COMP). The pathomolecular mechanisms of PSACH as a result of C-terminal globular region (CTD) mutations remain unclear. A heterozygous mutation (E559 K) in a Chinese family diagnosed with PSACH was reported in this study. To understand the pathogenesis of this mutation, we studied chondrogenic differentiation of patient menstrual blood-derived stem cells (MenSCs), and the impact of the mutation on structural changes of COMP was investigated using all-atom molecular dynamics simulation. The results suggested that the interactions with calcium and other molecules in the mutant structure were affected resulting in misfolding of the protein, which leads to ER stress and finally affects the survival of chondrocytes. The findings may promote the understanding of the pathomolecular mechanisms of PSACH, and possibly the development of drugs to treat the disease.

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软骨寡聚基质蛋白E559K突变的体外和计算机分析

假性软骨发育不全(PSACH)是一种常染色体显性遗传病，与软骨寡聚基质蛋白(COMP)基因突变有关。c端球状区(CTD)突变导致PSACH的病理分子机制尚不清楚。本研究报道了一个诊断为PSACH的中国家庭的杂合突变(e559k)。为了了解这种突变的发病机制，我们研究了患者经血源性干细胞(MenSCs)的软骨分化，并利用全原子分子动力学模拟研究了这种突变对COMP结构变化的影响。结果表明，突变结构中与钙等分子的相互作用受到影响，导致蛋白质错误折叠，从而导致内质网应激，最终影响软骨细胞的存活。这些发现可能会促进对PSACH病理分子机制的理解，并可能开发治疗该疾病的药物。

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来源期刊

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.