title: Functional characterization of novel telomerase RNA (TERC) mutations in patients with diverse clinical and pathological presentations.
abstract: OBJECTIVE
  Functional characterization of heterozygous TERC (telomerase RNA component) and TERT (telomerase reverse transcriptase) mutations found in autosomal dominant dyskeratosis congenita (DC) and aplastic anemia (AA) shows that telomerase function is defective and that this is associated with short telomeres. This leads to reduced cell longevity with maximal impact on tissues with high proliferate potential. The aim of this study was to establish the role of TERC in the pathophysiology of uncharacterized patients with AA with some features of DC.
  
  
  METHODS
  The TERC gene was screened for mutations by denaturing high performance liquid chromatography. To determine the functional significance of TERC mutations telomerase activity was assessed in an in vitro (TRAP) assay and telomere length of patients' samples was determined using Southern blot analysis. RESULTS This study led to the identification of four novel TERC mutations (G178A, C180T, D52-86 and G2C) and a recurrent TERC mutation (D110-113GACT).
  
  
  CONCLUSIONS
  Two of the de novo TERC mutations (G178A and C180T) found uniquely produce a clinical phenotype in the first generation, differing from previously published cases in which individuals in the first generation are usually asymptomatic. Curiously these mutations are located near the triple-helix domain of TERC. We also observed that the recurrent D110-113GACT can present with AA, myelodysplasia or leukemia. The D52-86 is associated with varied phenotypes including pulmonary disease (pulmonary fibrosis) as the first presentation. In summary, this study reports the functional characterization of several novel TERC mutations associated with varied hematologic and extra-hematologic presentations.
authors.affiliation: Academic Unit of Paediatrics, Institute of Cell and Molecular Science, Barts and The London,Queen Mary's School of Medicine and Dentistry, The Blizard Building, 4 Newark Street, London, E1 2AT, UK. a.f.marrone@qmul.ac.uk
authors.forename: Anna
authors.initials: A
authors.lastname: Marrone
authors.forename: Priya
authors.initials: P
authors.lastname: Sokhal
authors.forename: Amanda
authors.initials: A
authors.lastname: Walne
authors.forename: Richard
authors.initials: R
authors.lastname: Beswick
authors.forename: Michael
authors.initials: M
authors.lastname: Kirwan
authors.forename: Sally
authors.initials: S
authors.lastname: Killick
authors.forename: Mike
authors.initials: M
authors.lastname: Williams
authors.forename: Judith
authors.initials: J
authors.lastname: Marsh
authors.forename: Tom
authors.initials: T
authors.lastname: Vulliamy
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
mesh_terms: D000293:Adolescent; D000328:Adult; D000741:Anemia, Aplastic / Q000235:genetics*; D001483:Base Sequence; D002675:Child, Preschool; D019871:Dyskeratosis Congenita / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009508:Nevus, Pigmented / Q000235:genetics; D009690:Nucleic Acid Conformation; D010375:Pedigree; D010641:Phenotype; D010859:Pigmentation Disorders / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000235:genetics; D012313:RNA / Q000235:genetics*; D019098:Telomerase / Q000172:deficiency / Q000235:genetics*; D016615:Telomere / Q000648:ultrastructure*
chemical_list: C422952:telomerase RNA; D012313:RNA; D019098:Telomerase