Chromosomal breakage analysis in dyskeratosis congenita peripheral blood lymphocytes

Abstract

Summary. Dyskeratosis congenita (DC) is a rare inherited disorder characterized by reticulate skin pigmentation, nail dystrophy and mucosal leucoplakia. Bone marrow failure occurs in the majority of cases and there is a predisposition to malignancy. Following conflicting reports of increased spontaneous and induced chromosomal breakage in DC lymphocytes, we examined chromosomal breakage with and without clastogen treatment in 10 DC patients from six different families. Peripheral blood cultures were stimulated with phytohaemagglutinin and treated with three clastogenic agents and g-irradiation. There was no significant difference in the chromosomal breakage in DC lymphocytes with or without exposure to bleomycin, DEB, MMC or g-irradiation. DC can therefore be distinguished from Fanconi's anaemia in which lymphocytes show increased spontaneous and clastogen-induced chromosomal breakage.

Telomerase in the human organism

“…This molecular evidence for abnormally short telomeres is also supported at the cellular level by the premature proliferative senescence of cells from DKC patients in culture and by the age-and disease-dependent accumulation of chromosomes with aberrant fusions and rearrangements (Dokal et al, 1992). The premature telomere loss observed in DKC patients is particularly striking in the absence of any indication of a DNA repair de®ciency (Coulthard et al, 1998). Thus, there should not be an increase in proliferative demand linked to a higher rate of cell turnover.…”

Dyskeratosis congenita in all its forms

“…Some authors have reported excessive chromosome breakage in DC, either spontaneous ( Morrison, 1974) or induced ( Pai et al , 1989b ; DeBauche et al , 1990 ; Ning et al , 1992 ), whereas others disputed their findings ( Sirinavin & Trowbridge, 1975; Drachtman & Alter, 1992) with the result that, until recently, confusion existed over the susceptibility of DC cells to clastogenic agents. Coulthard et al (1998) chose a range of agents, based on previous reports suggesting susceptibility, to determine which agents would produce an increased level of breakage in DC lymphocytes over that seen in normal controls. This study demonstrated that there was no significant difference in chromosomal breakage between DC and normal lymphocytes with or without the use of bleomycin, diepoxybutane (DEB), MMC and γ‐irradiation.…”

Human Genome and Diseases:�Dyskeratosis congenita

“…Most of the tissues affected in DC patients (e. g. skin and BM) tend to be tissues derived from highly regenerative and rapidly dividing cells, and therefore DC appears to share features of a premature ageing syndrome, as well as being associated with BM failure syndromes [11]. In cases where diagnosis is inconclusive, the use of cellular sensitivity to clastogens can be used to distinguish between DC and FA patients [12]. Diagnosis of X-linked DC can also be aided by the ability to detect skewed Xchromosome inactivation patterns (XCIPs) in X-linked female carriers (see below).…”