PDF(Pubmed)
Abstract：
Adams-Oliver syndrome is a rare inherited condition characterized by scalp defects and limb abnormalities. It is caused by variants in different genes such as ARHGAP31. Here, we used an interdisciplinary approach to study a family with lower limb anomalies. We identified a novel variant in the ARHGAP31 gene that is predicted to result in a truncated protein with a constitutively activated catalytic site due to the loss of 688 amino acids involved in the C-terminal domain, essential for protein auto-inhibition. Pathogenic variants in ARHGAP31 exon 12, leading to a premature protein termination, are associated with Adams-Oliver syndrome. Bioinformatic analysis was useful to elucidate the impact of the identified genetic variant on protein structure. To better understand the impact of the identified variant, 3D protein models were predicted for the ARHGAP31 wild type, the newly discovered variant, and other pathogenetic alterations already reported. Our study identified a novel variant probably involved in Adams-Oliver syndrome and increased the evidence on the phenotypic variability in patients affected by this syndrome, underlining the importance of translational research, including experimental and bioinformatics analyses. This strategy represents a successful model to investigate molecular mechanisms involved in syndrome occurrence.
摘要：
亚当斯-奥利弗综合征是一种罕见的遗传性疾病，其特征是头皮缺陷和肢体异常。它是由不同基因如ARHGAP31的变异引起的。这里,我们采用跨学科的方法研究了一个下肢异常的家庭.我们在ARHGAP31基因中发现了一种新的变体，由于C末端结构域中涉及的688个氨基酸的丢失，该变体被预测会导致具有组成型活化催化位点的截短蛋白。蛋白质自抑制必不可少。ARHGAP31外显子12中的致病变异，导致蛋白质过早终止，与Adams-Oliver综合征有关.生物信息学分析可用于阐明鉴定的遗传变体对蛋白质结构的影响。为了更好地了解已识别变体的影响，预测了ARHGAP31野生型的3D蛋白模型，新发现的变种,和其他已经报道的致病改变。我们的研究发现了一种可能与Adams-Oliver综合征有关的新变异，并增加了受该综合征影响的患者的表型变异性的证据。强调转化研究的重要性，包括实验和生物信息学分析。该策略代表了研究综合征发生中涉及的分子机制的成功模型。
