Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
Laboratory of Endocrine and Metabolic Research, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Auxologico Italiano, Milan, Italy.
Front Endocrinol (Lausanne). 2023 Mar 16;14:1127312. doi: 10.3389/fendo.2023.1127312. eCollection 2023.
is required for thyroid function and its homozygous mutations cause a rare syndromic form of congenital hypothyroidism (CH). has a polymorphic polyalanine tract whose involvement in thyroid pathology is controversial. Starting from genetic studies in a CH family, we explored the functional role and involvement of variations in a large CH population.
We applied NGS screening to a large CH family and a cohort of 1752 individuals and validated these results by modeling and experiments.
A new heterozygous variant segregated with 14-Alanine tract homozygosity in 5 CH siblings with athyreosis. The p.L107V variant demonstrated to significantly reduce the FOXE1 transcriptional activity. The 14-Alanine-FOXE1 displayed altered subcellular localization and significantly impaired synergy with other transcription factors, when compared with the more common 16-Alanine-FOXE1. The CH group with thyroid dysgenesis was largely and significantly enriched with the 14-Alanine- homozygosity.
We provide new evidence that disentangle the pathophysiological role of FOXE1 polyalanine tract, thereby significantly broadening the perspective on the role of in the complex pathogenesis of CH. FOXE1 should be therefore added to the group of polyalanine disease-associated transcription factors.
对于甲状腺功能是必需的，其纯合突变导致罕见的综合征形式的先天性甲状腺功能减退症（CH）。 具有多态性多聚丙氨酸序列，其在甲状腺病理学中的参与存在争议。从 CH 家族的遗传研究开始，我们探讨了 变异在大型 CH 人群中的功能作用和参与。
我们对一个大型 CH 家族和 1752 个人的队列进行了 NGS 筛选，并通过 建模和 实验验证了这些结果。
在 5 名伴有无甲状腺的 CH 兄弟姐妹中，与 14-丙氨酸序列纯合性分离的新杂合 变体。与更常见的 16-丙氨酸-FOXE1 相比，p.L107V 变体显示出显著降低 FOXE1 转录活性的能力。与更常见的 16-丙氨酸-FOXE1 相比，14-丙氨酸-FOXE1 显示出改变的亚细胞定位，并显著损害与其他转录因子的协同作用。伴有甲状腺发育不良的 CH 组中，14-丙氨酸-纯合性显著且显著富集。
我们提供了新的证据，阐明了 FOXE1 多聚丙氨酸序列的病理生理作用，从而大大拓宽了 FOXE1 在 CH 复杂发病机制中的作用的观点。FOXE1 因此应添加到多聚丙氨酸疾病相关转录因子组中。
