title: Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita.
abstract: 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.
authors.affiliation: Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Armanios
authors.forename: Jiunn-Liang
authors.initials: JL
authors.lastname: Chen
authors.forename: Yen-Pei Christy
authors.initials: YP
authors.lastname: Chang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Brodsky
authors.forename: Anita
authors.initials: A
authors.lastname: Hawkins
authors.forename: Constance A
authors.initials: CA
authors.lastname: Griffin
authors.forename: James R
authors.initials: JR
authors.lastname: Eshleman
authors.forename: Alan R
authors.initials: AR
authors.lastname: Cohen
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Ada
authors.initials: A
authors.lastname: Hamosh
authors.forename: Carol W
authors.initials: CW
authors.lastname: Greider
mesh_terms: D000293:Adolescent; D000328:Adult; D020132:Anticipation, Genetic; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D019871:Dyskeratosis Congenita / Q000209:etiology / Q000235:genetics*; D005192:Family Health; D005260:Female; D018628:Gene Dosage; D005799:Genes, Dominant / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D019098:Telomerase / Q000172:deficiency / Q000235:genetics*; D016615:Telomere / Q000648:ultrastructure
chemical_list: D004268:DNA-Binding Proteins; D019098:Telomerase