Human telomere disease due to disruption of the CCAAT box of the TERC promoter.
Mutations in the coding region of telomerase complex genes can result in accelerated telomere attrition and human disease. Manifestations of telomere disease include the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia, acute myeloid leukemia, liver cirrhosis, and pulmonary fibrosis. Here, we describe a mutation in the CCAAT box (GCAAT) of the TERC gene promoter in a family in which multiple members had typical features of telomeropathy. The genetic alteration in this critical regulatory sequence resulted in reduced reporter gene activity and absent binding of transcription factor NF-Y, likely responsible for reduced TERC levels, decreased telomerase activity, and short telomeres. This is the first description of a pathogenic mutation in the highly conserved CCAAT box and the first instance of a mutation in the promoter region of TERC producing a telomeropathy. We propose that current mutation-screening strategies should include gene promoter regions for the diagnosis of telomere diseases. This clinical trial was registered at www.clinicaltrials.gov as #NCT00071045.
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Anna M
AM
Aalbers
Sachiko
S
Kajigaya
Marry M
MM
van den Heuvel-Eibrink
Vincent H J
VH
van der Velden
Rodrigo T
RT
Calado
Neal S
NS
Young
D000328:Adult; D000741:Anemia, Aplastic / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D016022:Case-Control Studies; D019871:Dyskeratosis Congenita / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008103:Liver Cirrhosis / Q000235:genetics; D008297:Male; D009154:Mutation / Q000502:physiology; D051839:NFI Transcription Factors / Q000378:metabolism*; D010375:Pedigree; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000235:genetics; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000473:pathology*
D051839:NFI Transcription Factors; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase