Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita.
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.
Armanios
Mary
M
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Chen
Jiunn-Liang
JL
Chang
Yen-Pei Christy
YP
Brodsky
Robert A
RA
Hawkins
Anita
A
Griffin
Constance A
CA
Eshleman
James R
JR
Cohen
Alan R
AR
Chakravarti
Aravinda
A
Hamosh
Ada
A
Greider
Carol W
CW
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
D004268:DNA-Binding Proteins; D019098:Telomerase