Dyskeratosis congenita: Advances in the understanding of the telomerase defect and the role of stem cell transplantation
Dyskeratosis congenita: Advances in the understanding of the telomerase defect and the role of stem cell transplantation
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DOI：
10.1111/j.1399-3046.2007.00721.x
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发表时间：
2007-09-01
影响因子：
1.3
通讯作者：
Dyskeratosis, Dokal I.
中科院分区：
文献类型：
--
作者：
de la Fuente, J.;Dyskeratosis, Dokal I.
DC是一种多系统骨髓衰竭综合征，表现出明显的临床和遗传异质性。x连锁，常染色体显性和常染色体隐性亚型是公认的。在x连锁DC （DKC1）中突变的基因编码一种高度保守的核仁蛋白，称为dyskerin。Dyskerin与小核仁核糖核蛋白颗粒中的小核仁RNA的H/ACA基序类相关，在核糖体RNA成熟过程中指导尿嘧啶向伪尿嘧啶的转化是重要的。Dyskerin还与TERC有关，TERC在端粒的维持中很重要。TERC突变已在常染色体显性DC患者和一部分再生障碍性贫血和骨髓增生异常患者中发现。近年来，在一些常染色体显性DC和再生障碍性贫血患者中发现了TERT的杂合突变。此外，患有严重多系统疾病Hoyeraal-Hreidarsson综合征的患者也被发现有DKC1突变。总的来说，这些观察结果表明，典型的DC， Hoyeraal-Hreidarsson综合征和再生障碍性贫血的一个子集是由于端粒酶的原发性缺陷。端粒和端粒酶在人类中的关键作用体现在这些患者的多系统异常中，包括恶性肿瘤发生率的增加。由于骨髓衰竭是死亡的主要原因，由于肺部和内皮并发症的高发，传统的同种异体移植尝试的成功率有限。然而，使用非清髓方案的结果有所改善，尽管随访时间太短，无法评估长期毒性和疾病的自然过程，可能端粒酶缺陷的纠正对这些患者的治疗至关重要。
DC is a multisystem bone marrow failure syndrome exhibiting marked clinical and genetic heterogeneity. X-linked, autosomal dominant and autosomal recessive subtypes are recognized. The gene mutated in X-linked DC (DKC1) encodes a highly conserved nucleolar protein called dyskerin. Dyskerin associates with the H/ACA motif class of small nucleolar RNAs in small nucleolar ribonucleoprotein particles that are important in guiding the conversion of uracil to pseudouracil during the maturation of ribosomal RNA. Dyskerin also associates with the TERC, which is important in the maintenance of telomeres. Mutations in TERC have been identified in patients with autosomal dominant DC and in a subset of patients with aplastic anemia and myelodysplasia. Recently, heterozygous mutations in TERT have been found in some patients with autosomal dominant DC and aplastic anemia. Additionally, patients with the severe multisystem disorder, Hoyeraal-Hreidarsson syndrome, have been found to have DKC1 mutations. Collectively, these observations have demonstrated that classical DC, Hoyeraal-Hreidarsson syndrome and a subset of aplastic anemia are due to a primary defect in telomerase. The critical role of telomeres and telomerase in humans is seen in the multisystem abnormalities found in these patients, including the increased incidence of malignancy. As bone marrow failure is the principal cause of death, conventional allografts have been attempted with limited success due to the high rate of pulmonary and endothelial complications. However, outcomes have improved with the use of non-myeloablative protocols, although the follow up is too short to evaluate long term toxicity and the natural course of the disease and it may be that correction of the telomerase defect is essential for the treatment of these patients.