Laboratory of Medical Genetics, Centro Diagnostico Italiano, 20147 Milan, Italy.
Department of Brain and Behavioral Science, Università Degli Studi di Pavia, 27100 Pavia, Italy.
Genes (Basel). 2024 Apr 24;15(5):536. doi: 10.3390/genes15050536.
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 . Here, we used an interdisciplinary approach to study a family with lower limb anomalies. We identified a novel variant in the 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 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.
Adams-Oliver 综合征是一种罕见的遗传性疾病，其特征为头皮缺陷和肢体异常。它是由不同基因的变异引起的，如. 在这里，我们采用了一种跨学科的方法来研究一个具有下肢异常的家族。我们在 基因中发现了一个新的变异，该变异预计会导致截短的蛋白质，由于涉及 C 末端结构域的 688 个氨基酸缺失，导致催化位点持续激活，而 C 末端结构域对于蛋白质的自动抑制是必不可少的。导致蛋白质提前终止的 外显子 12 中的致病性变异与 Adams-Oliver 综合征有关。生物信息学分析有助于阐明所鉴定的遗传变异对蛋白质结构的影响。为了更好地理解所鉴定的变异的影响，我们预测了 ARHGAP31 野生型、新发现的变异以及其他已报道的致病性改变的 3D 蛋白质模型。我们的研究鉴定了一个可能与 Adams-Oliver 综合征有关的新变异，并增加了受这种综合征影响的患者表型变异的证据，强调了转化研究的重要性，包括实验和生物信息学分析。这种策略代表了一种成功的模型，可以研究综合征发生中涉及的分子机制。
