title: Heterogeneous telomere defects in patients with severe forms of dyskeratosis congenita.
abstract: BACKGROUND
  Telomeres represent the tips of linear chromosomes. In human subjects telomere maintenance deficiency leads to dyskeratosis congenita (DC), a rare genetic disorder characterized by progressive bone marrow failure, accelerated aging, and cancer predisposition. Hoyeraal-Hreidarsson syndrome (HH) is a severe variant of DC in which an early onset of bone marrow failure leading to combined immunodeficiency is associated with microcephaly, cerebellar hypoplasia, and growth retardation.
  
  
  OBJECTIVE
  Limited information is available on the cellular and molecular phenotypes of cells from patients with HH. We analyzed fibroblasts and whole blood cells from 5 patients with HH, 3 of them of unknown molecular origin.
  
  
  METHODS
  Telomere length, cellular senescence rate, telomerase activity, telomeric aberration, and DNA repair pathways were investigated.
  
  
  RESULTS
  Although patients' cells exhibit dysfunctional telomeres, sharp differences in the telomeric aberrations and telomere lengths were noted among these patients. In some patients the dysfunctional telomere phenotype was unprecedented and associated with either normal telomere length or with telomeric aberrations akin to fragile telomeres. This result is of particular importance because the molecular diagnosis of these patients is primarily based on telomere length, which therefore misses a subset of patients with telomere dysfunction.
  
  
  CONCLUSIONS
  These observations provide the notions that (1) various telomere defects can lead to similar clinical features, (2) telomere dysfunction in cells from patients with DC/HH is not always associated with short telomeres, and (3) additional factors, likely involved in telomere protection rather than in length regulation, are responsible for a subset of DC/HH.
authors.affiliation: INSERM, U768, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Touzot
authors.forename: Laetitia
authors.initials: L
authors.lastname: Gaillard
authors.forename: Nadia
authors.initials: N
authors.lastname: Vasquez
authors.forename: Tangui
authors.initials: T
authors.lastname: Le Guen
authors.forename: Yves
authors.initials: Y
authors.lastname: Bertrand
authors.forename: Jean
authors.initials: J
authors.lastname: Bourhis
authors.forename: Thierry
authors.initials: T
authors.lastname: Leblanc
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
mesh_terms: D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D004260:DNA Repair; D019871:Dyskeratosis Congenita / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008831:Microcephaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017422:Sequence Analysis, DNA; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism* / Q000473:pathology; D034501:Telomere-Binding Proteins / Q000235:genetics
chemical_list: C440868:TINF2 protein, human; D034501:Telomere-Binding Proteins; D004247:DNA; D019098:Telomerase