Chromosomal breakage syndromes

Immunodeficiency and chromosomal instability are markers of ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS), which together with Bloom syndrome and xeroderma pigmentosum belong to the group of syndromes with chromosomal instability. The genes whose mutations cause the development of AT and NBS are ATM (Ataxia-Teleangiectasia Mutated) and NBSl, respectively. ATM codes for the synthesis of the kinase of the same name, and NBSl for nibrin. Both proteins are involved in the repair of double-stranded DNA breaks and the regulation of the cell cycle. Cells from patients with A-T and NBS have a similar phenotype and are characterized by increased sensitivity to radiation, cell cycle defects, but clinical manifestations and immunological disorders have significant differences, although both diseases are characterized by an increased incidence of malignant tumors and spontaneous chromosomal instability and chromosomal breaks, mainly involving chromosomes 7 and 14.

It is known that the cell cycle is divided into 4 phases: mitosis (M) and DNA synthesis (S), separated by two breaks G1 and G2. The cell cycle sequence is as follows G1-S-G2-M. After exposure to ionizing radiation, double-stranded DNA breaks occur. If DNA is repaired, the cell cycle is restored, if not, the cell dies by apoptosis or a mutant clone develops. Normally, the cell cycle can be blocked at two critical points when exposed to radiation - the transition from G1 to S and / or from G2 to M phase. With A-T and NBS, cell cycle control at critical points is disrupted. The ATM protein plays a critical role in activating cell cycle regulation pathways that occur both in G1 and G2 phases. The NBS1 gene encodes the nibrin protein, which, like ATM, is involved in cell cycle regulation.

Normally, double-stranded DNA breaks occur during the V(D)J recombination of immunoglobulin genes and the T-cell receptor, during crossing over, and during meiosis. Processes resembling the recombination of immunoglobulin genes occur during the maturation of neurons in the brain. It is obvious that many clinical and immunological manifestations in patients with NBS and A-T, such as disorders in the synthesis of immunoglobulins, the function of the genitals and the nervous system, are associated with DNA reparation defects in these cases.

A very rare combination of the classic A-T phenotype with microcephaly and ATM mutations is found, and this syndrome is called "AT-Fresno". In essence, AT-Fresno is a phenotype that reflects the association of A-T with Nijmegen syndrome.