Cell and Molecular Biology Program, Biomedical Graduate Studies, Medical Scientist Training Program, Philadelphia, Pennsylvania.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Ann N Y Acad Sci. 2018 Apr;1418(1):56-68. doi: 10.1111/nyas.13692.
The consequences of telomere dysfunction are most apparent in rare inherited syndromes caused by genetic deficiencies in factors that normally maintain telomeres. The principal disease is known as dyskeratosis congenita (DC), but other syndromes with similar underlying genetic defects share some clinical aspects with this disease. Currently, there are no curative therapies for these diseases of telomere dysfunction. Here, we review recent findings demonstrating that dysfunctional (i.e., uncapped) telomeres can downregulate the WNT pathway, and that restoration of WNT signaling helps to recap telomeres by increasing expression of shelterins, proteins that naturally bind and protect telomeres. We discuss how these findings are different from previous observations connecting WNT and telomere biology, and discuss potential links between WNT and clinical manifestations of the DC spectrum of diseases. Finally, we argue for exploring the use of WNT agonists, specifically lithium, as a possible therapeutic approach for patients with DC.
端粒功能障碍的后果在由正常维持端粒的因子的遗传缺陷引起的罕见遗传性综合征中最为明显。主要疾病称为先天性角化不良（DC），但具有相似潜在遗传缺陷的其他综合征与这种疾病具有一些临床方面的相似性。目前，这些端粒功能障碍疾病尚无治愈疗法。在这里，我们回顾了最近的发现，这些发现表明功能失调（即无盖）端粒可以下调 WNT 途径，并且恢复 WNT 信号有助于通过增加庇护素的表达来重新捕获端粒，庇护素是天然结合和保护端粒的蛋白质。我们讨论了这些发现与以前将 WNT 与端粒生物学联系起来的观察结果有何不同，并讨论了 WNT 与 DC 疾病谱的临床表现之间的潜在联系。最后，我们认为应该探索使用 WNT 激动剂（特别是锂）作为 DC 患者的一种可能的治疗方法。
