For the first time, a previously unknown immunodeficiency syndrome could be detected, which is based on a reduced functionality of the enzyme complex Polymerase delta. This provides important insights into adaptive immunity and cancer development.
The DNA polymerase delta enzyme is an essential control unit in DNA replication. If its function is impaired due to mutations, this leads to genomic instability, neurological developmental disorders, and immunodeficiency.
Genes are the basic building blocks of life and therefore of essential importance. The factors responsible for their multiplication are therefore present in almost all living beings in a very similar way and have hardly changed over the millennia. One such factor is the polymerase delta. This enzyme complex is not only a central element for DNA replication, but also for the stabilization of the genome and the regulation of the cell cycle. Polymerase delta consists of four building blocks: POLD1 and the additional subunits POLD2, POLD3 and POLD4. Organisms with severe disorders of such DNA polymerases are often nonviable, which naturally makes their research more difficult.
Now scientists have succeeded for the first time in identifying two patients with a novel immunodeficiency syndrome based on a reduced functionality of polymerase delta. Specifically, biallelic germline mutations, i.e. gene mutations inherited from both parents, could be detected in POLD1 and POLD2 in unrelated patients. In both cases, this led to an immunodeficiency syndrome with recurrent respiratory infections, skin problems, and neurological developmental disorders.
A closer examination of the disease mechanisms revealed that the cell cycle in the lymphocytes of both patients was impaired. DNA replication, for example, resulted in an increase in copying errors, which led to warning markings on the DNA in the cell and were thus responsible for the dysfunction of the cell cycle.
Since in this case an immune-specific factor is not disturbed as in other immunodeficiency syndromes, the underlying disease mechanisms of this syndrome provide interesting additional key information for other clinical cases such as cancer in children.
Although immune cells were particularly affected, the mechanism by which polymerase delta controls genome duplication is relevant for the function of all cells. A disorder can have dramatic consequences for cell growth. It is known that certain mutations in POLD1 contribute to the development of the "mutator phenotype", which contributes to genetic instability and thus to the development of cancer. Accordingly, POLD1 is classified as a highly dangerous cause of cancer in international classification. The congenital POLD1/2 mutations described here, on the other hand, lead to reduced intrinsic activity (the "actual task") of the polymerase delta, with a possibly increased tendency to develop cancer, that is, in a way, a cancer predisposition syndrome.
Original publication:
Conde CD et al., Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress. J Clin Invest. 2019; pii: 128903. doi:10.1172/JCI128903