Analysis of F9 point mutations and their correlation to severity of haemophilia B disease
Analysis of F9 point mutations and their correlation to severity of haemophilia B disease
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DOI：
10.1111/j.1365-2516.2012.02848.x
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发表时间：
2012-11-01
期刊：
影响因子：
3.9
通讯作者：
Kimchi-Sarfaty, C.
中科院分区：
文献类型：
--
作者：
Hamasaki-Katagiri, N.;Salari, R.;Kimchi-Sarfaty, C.
血友病B是一种由功能性凝血因子IX缺乏引起的X连锁隐性疾病，几乎完全是由F9基因的突变导致的。我们试图确定一些特征，以便区分那些导致严重疾病症状的突变和那些导致非严重疾病症状的突变。为了实现这一目标，我们对已报道的F9基因的点突变进行了统计分析。这些分析包括：mRNA自由能的潜在局部变化、密码子使用情况、突变氨基酸的电荷和类型、突变相对于蛋白质二级结构和功能域的位置以及氨基酸的进化保守性得分。威尔科克森符号秩检验表明，导致严重疾病和非严重疾病的突变在对小mRNA片段自由能和进化上保守的氨基酸的影响方面存在极显著差异。我们的结果表明，mRNA水平的信息以及氨基酸的保守性与疾病的严重程度密切相关。这项研究表明，计算工具可用于描述与点突变相关的血友病B的严重程度，并表明它们在预测重组蛋白序列变化结果方面的实用性。
Haemophilia B is an X-linked recessive disorder caused by deficiency of functional coagulation factor IX, which results almost exclusively from mutations in the F9 gene. We sought to determine features, which could distinguish between mutations that cause severe disease symptoms from those that cause non-severe disease symptoms. Towards this objective, we have performed a statistical analysis of reported point mutations in F9. These include: potential local changes in mRNA free energy, codon usage, charge and type of mutated amino acid, location of the mutation with regard to protein secondary structure and functional domain and amino acids' evolutionary conservation scores. Wilcoxon signed-rank tests showed highly significant differences between severe and non-severe disease causing mutations in their effect on free energy of small mRNA fragments and evolutionarily conserved amino acids. Our results suggest that information at the mRNA level as well as conservation of the amino acid correlate well with disease severity. This study demonstrates that computational tools may be used to characterize the severity of haemophilia B associated with point mutations and suggests their utility in predicting the outcome of sequence changes in recombinant proteins.