Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita
Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita
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DOI：
10.1073/pnas.0508124102
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发表时间：
2005-11-01
影响因子：
11.1
通讯作者：
Greider, CW
中科院分区：
文献类型：
--
作者：
Armanios, M;Chen, JL;Greider, CW
先天性角化不良是一种罕见的遗传性疾病，其特征是异常的皮肤表现。这种疾病的发病率和死亡率通常是由于骨髓衰竭，但也会发生特发性肺纤维化和癌症易感性增加。常染色体显性遗传性角化不良家族表现出预期性，并在端粒酶RNA基因中存在突变。我们确定了一个三代常染色体显性遗传性先天性角化不良，预期和端粒缩短的家系。我们发现，无效突变的基序D的逆转录酶结构域的蛋白组分端粒酶，hTERT，与这种表型。这种突变导致端粒酶的单倍不足，尽管存在端粒酶，端粒仍会缩短。这一发现强调了端粒维持和端粒酶剂量对维持组织增殖能力的重要性，并与理解年龄相关变化的机制有关。
Dyskeratosis congenita is a rare inherited disorder characterized by abnormal skin manifestations. Morbidity and mortality from this disease is usually due to bone marrow failure, but idiopathic pulmonary fibrosis and an increased cancer predisposition also occur. Families with autosomal dominant dyskeratosis congenital display anticipation and have mutations in the telomerase RNA gene. We identified a three-generation pedigree with autosomal dominant dyskeratosis congenita, anticipation, and telomere shortening. We show that a null mutation in motif D of the reverse transcriptase domain of the protein component of telomerase, hTERT, is associated with this phenotype. This mutation leads to haploinsufficiency of telomerase, and telomere shortening occurs despite the presence of telomerase. This finding emphasizes the importance of telomere maintenance and telomerase dosage for maintaining tissue proliferative capacity and has relevance for understanding mechanisms of age-related changes.