A truncated human chromosome 16 associated with α thalassaemia is stabilized by addition of telomeric repeat (TTAGGG)n

Abstract

The instability of chromosomes with breaks induced by X-irradiation led to the proposal that the natural ends of chromosomes are capped by a specialized structure, the telomere. Telomeres prevent end-to-end fusions and exonucleolytic degradation, enable the end of the linear DNA molecule to replicate, and function in cell division. Human telomeric DNA comprises approximately 2-20 kilobases (kb) of the tandemly repeated sequence (TTAGGG)n oriented 5'----3' in towards the end of the chromosome, interspersed with variant repeats in the proximal region. Immediately subtelomeric lie families of unrelated repeat motifs (telomere-associated sequences) whose function, if any, is unknown. In lower eukaryotes the formation and maintenance of telomeres may be mediated enzymatically (by telomerase) or by recombination; in man the mechanisms are poorly understood, although telomerase has been identified in HeLa cells. Here we describe an alpha thalassaemia mutation associated with terminal truncation of the short arm of chromosome 16 (within band 16p13-3) to a site 50 kb distal to the alpha globin genes, and show that (TTAGGG)n has been added directly to the site of the break. The mutation is stably inherited, proving that telomeric DNA alone is sufficient to stabilize the broken chromosome end. This mechanism may occur in any genetic disease associated with chromosome truncation.

Ring chromosome formation as a novel escape mechanism in patients with inverted duplication and terminal deletion

“…Telomere healing can be accomplished by addition of human telomeric tandem repeat sequence to broken chromosome ends 20 Examples of constitutional telomere capture are less common and is only reported a few times. 22,23 Among the several inverted duplication/deletion events reported, 7 -9,15 -19,23 in a single case the broken chromosome was proven to be repaired with telomere capture.…”

Unmasking of a hemizygous WFS1 gene mutation by a chromosome 4p deletion of 8.3 Mb in a patient with Wolf–Hirschhorn syndrome

“…18 Addition or capture of telomere repeats (TTAGGG n ) results in telomere regeneration. 19 The most frequently occurring inv dup del involves 8p, and is mediated by illegitimate recombination between two olfactory receptor gene clusters in 8p23.1 during meiosis in female carriers of a 4.7 Mb 8p inversion polymorphism. 20 Although olfactory receptor gene clusters and their corresponding inversion polymorphism are also located in 4p16.3, involvement of these gene clusters is unlikely in our case as the distal break occurred in 4p16.1.…”

Telomerase activity in a specific cell subset co-expressing integrinβ1/EGFR but not p75NGFR/bcl2/integrin β4 in normal human epithelial cells

“…In the absence of telomerase, the length of the reiterated telomere sequences, (TTAGGG)n in human, should processively shorten because of the end replication problem (Watson, 1972). Using cultured cells and cell lines, evidence for a close correlation between telomere length and the capacity of proliferative potentials has been documented (Allshire et al, 1988(Allshire et al, , 1989Moyzis et al, 1988;Harley et al, 1990;Harley, 1991Harley, , 1995Hastie et al, 1990;Wilkie et al, 1990;Yu et al, 1990;Allsopp et al, 1992;Levy et al, 1992;Counter et al, 1992Counter et al, , 1994aKruk et al, 1995). On the other hand, it has been demonstrated that activated telomerase is evidently associated with more than 85% of cancer cells and the majority of established cell lines but is undetectable in normal cellular counterparts (Kim et al, 1994).…”