A detailed analysis of the T lymphocytes from a patient with a rare immunodeficiency has offered new clues about an unusual process by which spontaneous mutations occur that repair the genetic defect that causes the disease.
The study, published in the journal Blood, suggests that the likelihood of changes that reverse pathological mutations in primary immunodeficiencies depends on the intrinsic mutability of these genes.
The patient's T cells had a gene defect that caused a malfunction of the lymphocytes and severe immunodeficiency. Nonetheless, the researchers observed that a small population of the patient’s T cells had recovered the expression and function of that gene.
"It had been reported that in some immunodeficiencies, some affected lymphocytes were able recover the original sequence and thus their function and viability, in a process called reversion, but the reason for this process was unclear. In a detailed analysis of the sequence of the damaged gene in the T cells of this patient, we observed considerable sequence variability. This led us to wonder if the incidence of reversion might reflect high gene mutability," explains Hugh Reyburn, lead author of the study.
A computer analysis compared affected genes in primary immunodeficiencies for which reversions had been described, and mutated genes in immunodeficiencies for which no reversions had been reported. This analysis confirmed a high rate of specific variation of the coding region of the first group of genes. These data support the hypothesis that the intrinsic mutability of a gene determines the probability of somatic changes able to reverse the genetic defect that causes the pathology.
- Alfonso Blázquez-Moreno, Adriana Pérez-Portilla, Miriam Agúndez-Llaca, Daniela Dukovska, Mar Valés-Gómez, Cigdem Aydogmus, Aydan Ikinciogullari, José R. Regueiro and Hugh T. Reyburn. Analysis of the recovery of CD247 expression in a PID patient: Insights into the spontaneous repair of defective genes. Blood 2017 :blood-2017-01-762864