[Syndrome of premature ageing in ataxia-telangiectasia patients]

Ataxia-telangiectasia (AT), a genetic disorder due to mutation of gene atm characterized by progressive neurological abnormalities in combination with oculocutaneous telangiectasias, immunodeficiency, and increased frequency of malignant formations, is inherited according to autosome recessive mechanism. Cells of the patients with AT show increased radio sensitivity and some markers of premature ageing. The telomere lengths are sharply shortened in these cells already from the birth. We studied radio sensitivity (at the dose 2 Gy) and manifestations of premature ageing markers in cultured skin fibroblasts obtained from two unrelated AT patients and their heterozygous parents. We have shown that all the markers studied, that is HP1-gamma, phosphorylation of the histone variant H2AX (gamma-H2AX), and focuses 53BP1, indicate premature ageing of both the patients' and their blood relatives' cells. However, cells of the heterozygous carriers express premature ageing to a less extent. Investigation of the repair process characteristics (the amount of gamma-H2AX and the deal of cells with focuses 53BP1 in their nuclei) after X-ray irradiation has given following results: the patients' cells complete repair only half even in 24 after irradiation, while the healthy donor's cells complete repair in 24 h. Heterozygous cells also reliably differ from healthy donor's cells. Only in the case of apoptosis marker, p21, heterozygous cells do not differ from normal cells, whereas the patients' cells differ significantly. It has been noted that the mutation of gene atm is related to suppression of DNA double-strand breaks (DSBs) repair systems, which, in its turn, is in accordance with the increased radio sensitivity and premature ageing at the cell level in the AT families.