TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements

Abstract

Dyskeratosis congenita (DC) is a rare inherited form of bone marrow failure (BMF) caused by mutations in telomere maintaining genes including TERC and TERT. Here we studied the prevalence of TERC and TERT gene mutations and of telomere shortening in an unselected population of patients with BMF at our medical center and in a selected group of patients referred from outside institutions. Less than 5% of patients with BMF had pathogenic mutations in TERC or TERT. In patients with BMF, pathogenic TERC or TERT gene mutations were invariably associated with marked telomere shortening (Ͻ Ͻ 1st percentile) in peripheral blood mononuclear cells (PBMCs). In asymptomatic family members, however, telomere length was not a reliable predictor for the presence or absence of a TERC or TERT gene mutation. Telomere shortening was not pathognomonic of DC, as approximately 30% of patients with BMF due to other causes had PBMC telomere lengths at the 1st percentile or lower. We conclude that in the setting of BMF, measurement of telomere length is a sensitive but nonspecific screening method for DC. IntroductionDyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome (IBMFS). Patients with DC typically present with progressive bone marrow failure (BMF) and the classic triad of mucocutaneous features, including abnormal pigmentation, dystrophic nail changes, and leukoplakia of the oral mucosa. 1-3 Disease penetrance is highly variable, ranging from hardly detectable, to severe forms causing death in early childhood, as seen in Hoyeraal Hreidarson (HH) syndrome. With the identification of 6 genes that when mutated can cause DC (DKC1, TERC, TERT, NOP10, NHP2, and TINF2) 4-9 and the availability of genetic testing, it has become increasingly evident that the classic mucocutaneous features are only present in a small proportion of patients with DC, suggesting that a diagnosis based on the presence of these manifestations alone is likely to overlook a significant proportion of patients with DC. 10 Screening for pathogenic mutations is expensive, time-consuming, and, in approximately half of patients, inconclusive. Thus, using the methods currently available, mutation screening does not seem to be a suitable screening test for the diagnosis of DC. However, all genes implicated in DC are involved in telomere maintenance, suggesting that dysfunctional and excessively short telomeres are the common denominator in this disease and that short and dysfunctional telomeres play an important role in the pathogenesis of disease in patients with DC.Telomeres are complex DNA-protein structures at the end of chromosomes. 11,12 In most eukaryotes including humans, telomeric DNA is composed of guanine-rich DNA repeat sequences. 13 Telomeres shorten with each cell division. 14 When telomeres become critically short, a DNA damage response is activated, causing cell cycle arrest or cell death. 15 In humans, telomerasebased telomere elongation is the major mechanism that counteracts this process of continuous telomere shortening. 16,17 ...

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

“…Finally, mutations of the regulator of telomere elongation helicase 1 (RTEL1 gene) have been identified in patients with severe autosomal recessive DC [35] (Table 1). DC is a rare inherited disorder characterized by a typical triad of clinical manifestations: skin hyperpigmentation, oral leukoplakia and nail dystrophy [26]. The majority of cases (>80 %) occur in children and are diagnosed usually about the age of ten when the children start presenting bone marrow failure together with the previously described clinical triad.…”

Nouvelles formes de dyskératoses congénitales

“…La mesure de la longueur des télomères dans les cellules du sang périphérique constitue à ce jour le test de dépistage de référence pour l'identification des patients atteints de DC du fait de la relation communément admise entre DC/aplasie médullaire et télomères anormalement courts [24]. Cette mesure peut s'effectuer par Southern blot, PCR (polymerase chain reaction) quantitative ou FISH (fluorescence in situ hybridization) quantitatif parfois couplé à la cytométrie de flux (flow-FISH) [24][25][26].…”

“…Cette mesure peut s'effectuer par Southern blot, PCR (polymerase chain reaction) quantitative ou FISH (fluorescence in situ hybridization) quantitatif parfois couplé à la cytométrie de flux (flow-FISH) [24][25][26]. La longueur des télomères des leucocytes diminuant avec l'âge chez les individus sains, ce test diagnostic se révèle plus discriminant chez les enfants que chez les adultes [26].…”

“…Ce test est donc peu sensible pour distinguer un patient d'un individu sain. Ceci est particulièrement vrai au sein des familles de patients atteints de DC chez qui les télomères courts, mais non la mutation pathogène, peuvent être hérités du parent atteint [24]. Ainsi, en l'absence d'aplasie médullaire, les tests génétiques restent incontournables pour affirmer le diagnostic de DC.…”

Dyskeratosis congenita

“…Another group recently concluded that telomere length was sensitive but not specific in screening for DC [38]. The flow-FISH method used to determine telomere length differed from previously established methods in several ways [3;39;40].…”