title: A mutation in the H/ACA box of telomerase RNA component gene (TERC) in a young patient with myelodysplastic syndrome.
abstract: BACKGROUND
  Telomeres are repeated sequences (the hexanucleotide TTAGGG in vertebrates) located at chromosome ends of eukaryotes, protecting DNA from end joining or degradation. Telomeres become shorter with each cell cycle, but telomerase, a ribonucleoprotein complex, alleviates this attrition. The telomerase RNA component (TERC) is an essential element of telomerase, serving as a template for telomere elongation. The H/ACA domain of TERC is indispensable for telomere biogenesis. Mutations in the telomerase components allow accelerated telomere loss, resulting in various disease manifestations, including bone marrow failure. To date, this is the first detailed report of an H-box mutation in TERC that is related to human disease.
  
  
  METHODS
  A 26-year-old man with myelodysplastic syndrome (MDS) had very short telomeres. Sequencing identified a single heterozygous mutation in the H box of the patient's TERC gene. The same mutation was also present in his father and his son, demonstrating that it was germline in origin. The telomere length in the father's blood was shorter compared to age-matched healthy controls, while it was normal in the son and also in the sperm cells of the patient. In vitro experiments suggested that the mutation was responsible for the telomere shortening in the patient's leukocytes and contributed to the pathogenesis of bone marrow failure in our patient.
  
  
  CONCLUSIONS
  We analyzed a mutation (A377G) in the H box of TERC in a young MDS patient who had significantly short-for-age telomeres. As telomeres protect chromosomes from instability, it is highly plausible that this genetic lesion was responsible for the patient's hematological manifestations, including marrow failure and aneuploidy in the hematopoietic stem cell compartment.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bldg 10-CRC, Rm 3E-5216, 9000 Rockville Pike, Bethesda, MD 20892, USA. yueda.maro@gmail.com.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Ueda
authors.forename: Rodrigo T
authors.initials: RT
authors.lastname: Calado
authors.forename: Anna
authors.initials: A
authors.lastname: Norberg
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kajigaya
authors.forename: Göran
authors.initials: G
authors.lastname: Roos
authors.forename: Eva
authors.initials: E
authors.lastname: Hellstrom-Lindberg
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
mesh_terms: D000328:Adult; D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D009690:Nucleic Acid Conformation; D059372:Nucleotide Motifs; D010375:Pedigree; D011485:Protein Binding; D021381:Protein Transport; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D059506:Telomere Shortening
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase