Heterogeneous telomere defects in patients with severe forms of dyskeratosis congenita

摘要: 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 severe variant DC in which an early onset failure leading combined immunodeficiency associated with microcephaly, cerebellar hypoplasia, growth retardation. Objectives Limited information available on cellular molecular phenotypes cells from patients HH. We analyzed fibroblasts whole blood 5 HH, 3 them unknown origin. Methods Telomere length, senescence rate, telomerase activity, telomeric aberration, DNA repair pathways were investigated. Results Although patients' exhibit dysfunctional telomeres, sharp differences aberrations lengths noted among these patients. some phenotype was unprecedented either normal length or akin fragile telomeres. This result particular importance because diagnosis primarily based therefore misses subset dysfunction. Conclusion These observations provide notions that (1) various defects can lead similar clinical features, (2) dysfunction DC/HH not always short (3) additional factors, likely involved protection rather than regulation, are responsible for DC/HH.