Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita

M Armanios, JL Chen, YPC Chang… - Proceedings of the …, 2005 - National Acad Sciences
M Armanios, JL Chen, YPC Chang, RA Brodsky, A Hawkins, CA Griffin, JR Eshleman
Proceedings of the National Academy of Sciences, 2005National Acad Sciences
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 …
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.
National Acad Sciences