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Abstract：
Setleis syndrome is characterized by bitemporal scar-like lesions and other characteristic facial features. It results from recessive mutations that truncate critical functional domains in the basic helix-loop-helix (bHLH) transcription factor, TWIST2, which regulates expression of genes for facial development. To date, only four nonsense or small deletion mutations have been reported. In the current report, the clinical findings in a consanguineous Turkish family were characterized. Three affected siblings had the characteristic features of Setleis syndrome. Homozygosity for the first TWIST2 missense mutation, c.326T>C (p.Leu109Pro), was identified in the patients. In silico analyses predicted that the secondary structure of the mutant protein was sustained, but the empirical force field energy increased to an unfavorable level with the proline substitution (p.Leu109Pro). On a crystallographically generated dimer, p.Leu109 lies near the dimer interface, and the proline substitution is predicted to hinder dimer formation. Therefore, p.Leu109Pro-TWIST2 alters the three dimensional structure and is unable to dimerize, thereby hindering the binding of TWIST2 to its target genes involved in facial development.
摘要：
Setleis综合征的特征是双颞叶瘢痕样病变和其他特征性面部特征。它是由隐性突变导致的，这些突变截短了基本螺旋-环-螺旋（bHLH）转录因子中的关键功能域，TWIST2，调节面部发育基因的表达。迄今为止,仅报道了四个无义或小缺失突变。在当前的报告中,对一个近亲土耳其家庭的临床发现进行了表征。三个受影响的兄弟姐妹具有Setleis综合征的特征。第一个TWIST2错义突变的纯合性，c.326T>C（p。Leu109Pro)，在患者中发现。在电脑分析预测，突变蛋白的二级结构是持续的，但是随着脯氨酸替代，经验力场能量增加到不利水平（p。Leu109Pro）。在晶体学产生的二聚体上，p.Leu109位于二聚体界面附近，预测脯氨酸取代会阻碍二聚体的形成。因此,p.Leu109Pro-TWIST2改变了三维结构，无法二聚化，从而阻碍TWIST2与其参与面部发育的靶基因的结合。
