Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA; Center for Genome Integrity, Washington University in St. Louis, St. Louis, MO, USA; Center of Regenerative Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Trends Mol Med. 2022 Oct;28(10):882-891. doi: 10.1016/j.molmed.2022.08.001. Epub 2022 Sep 1.
Telomere biology disorders (TBDs) are a group of rare diseases caused by mutations that impair telomere maintenance. Mutations that cause reduced levels of TERC/hTR, the telomerase RNA component, are found in most TBD patients and include loss-of-function mutations in hTR itself, in hTR-binding proteins [NOP10, NHP2, NAF1, ZCCHC8, and dyskerin (DKC1)], and in proteins required for hTR processing (PARN). These patients show diverse clinical presentations that most commonly include bone marrow failure (BMF)/aplastic anemia (AA), pulmonary fibrosis, and liver cirrhosis. There are no curative therapies for TBD patients. An understanding of hTR biogenesis, maturation, and degradation has identified pathways and pharmacological agents targeting the poly(A) polymerase PAPD5, which adds 3'-oligoadenosine tails to hTR to promote hTR degradation, and TGS1, which modifies the 5'-cap structure of hTR to enhance degradation, as possible therapeutic approaches. Critical next steps will be clinical trials to establish the effectiveness and potential side effects of these compounds in TBD patients.
端粒生物学疾病（TBDs）是一组由突变引起的罕见疾病，这些突变会损害端粒的维持。导致 TERC/hTR 水平降低的突变存在于大多数 TBD 患者中，包括 hTR 本身、hTR 结合蛋白[NOP10、NHP2、NAF1、ZCCHC8 和 dyskerin (DKC1)]以及 hTR 加工所需的蛋白[PARN]的失活突变。这些患者表现出多种临床表现，最常见的是骨髓衰竭（BMF）/再生障碍性贫血（AA）、肺纤维化和肝硬化。目前尚无针对 TBD 患者的治愈疗法。对 hTR 生物发生、成熟和降解的了解已经确定了针对多聚（A）聚合酶 PAPD5 的途径和药理学制剂，PAPD5 向 hTR 添加 3'-寡腺苷酸尾巴以促进 hTR 降解，以及 TGS1，它修饰 hTR 的 5'-帽结构以增强降解，这可能是一种治疗方法。下一步将是临床试验，以确定这些化合物在 TBD 患者中的有效性和潜在副作用。
