Armanios Mary, Chen Jiunn-Liang, Chang Yen-Pei Christy, Brodsky Robert A, Hawkins Anita, Griffin Constance A, Eshleman James R, Cohen Alan R, Chakravarti Aravinda, Hamosh Ada, Greider Carol W
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15960-4. doi: 10.1073/pnas.0508124102. Epub 2005 Oct 24.
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 congenita 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.
先天性角化不良是一种罕见的遗传性疾病，其特征为皮肤表现异常。该疾病的发病率和死亡率通常归因于骨髓衰竭，但也会出现特发性肺纤维化和癌症易感性增加的情况。常染色体显性遗传性先天性角化不良家族呈现出遗传早现现象，并且端粒酶RNA基因存在突变。我们鉴定出一个具有常染色体显性遗传性先天性角化不良、遗传早现和端粒缩短的三代家系。我们发现，端粒酶蛋白质成分hTERT逆转录酶结构域基序D中的一个无效突变与这种表型相关。该突变导致端粒酶单倍剂量不足，尽管存在端粒酶，但仍会发生端粒缩短。这一发现强调了端粒维持和端粒酶剂量对于维持组织增殖能力的重要性，并且对于理解与年龄相关变化的机制具有重要意义。
