CeMM: Novel immunodeficiency syndrome amidst immunity and carcinogenesis

For the first time, a study led by Kaan Boztug, Scientific Director of St. Anna Children's Cancer Research Institute, unveils a hitherto unknown immune deficiency syndrome, which is based on a reduced functionality of the enzyme complex polymerase δ, an essential controller in DNA replication. Mutations affecting its function lead to genomic instability, neurodevelopmental disorders and immunodeficiency. The study was recently published in the prestigious Journal of Clinical Investigation and brings important insights into adaptive immunity and carcinogenesis.

Genes are the basic building blocks of life and, consequently, essential to all living organisms. The factors, which are responsible for their duplication, are very similar in almost all living organisms and have hardly changed over thousands of years. One of these factors is polymerase δ. This enzyme complex is a key element not only for DNA replication, but also for genome stabilization and cell cycle regulation. Polymerase δ is composed of four building blocks: POLD1 and the additional subunits POLD2, POLD3 and POLD4. Organisms with severe disruption of these DNA polymerases are often not viable, which makes research difficult.

Led by Kaan Boztug, researchers from LBI-RUD, CeMM and MedUni Vienna, together with collaborators from the University of Istanbul and the University of Leiden, could identify two unrelated patients with a novel immunodeficiency syndrome based on a reduced functionality of polymerase δ. Specifically, they detected biallelic germline mutations, i.e. gene mutations inherited from both parents, in POLD1 and POLD2. In both cases, these mutations resulted in an immunodeficiency syndrome with recurrent respiratory infections, skin problems, and neurodevelopmental disorders. Closer examination of the disease mechanisms revealed that the cell cycle was impaired in the lymphocytes of both patients. The number of copying errors in DNA increased, which lead to warning tags in the DNA of the cell, and, therefore, causes cell cycle dysfunction.

Particularly noteworthy is that the study provides also key information for other diseases such as childhood cancer: Unlike in other immunodeficiency syndromes with a shortage of an immune-specific factor, the underlying disease mechanism is a deficiency of a basic function of the cell. Although the deficiency particularly affected immune cells, the replication control mechanism of polymerase δ is relevant to the function of all cells. A disorder can have dramatic consequences in the balance of cell growth. It is known that certain mutations in POLD1 lead to the so-called "mutator phenotype", which contributes to genetic instability and is found in many human cancers. Accordingly, POLD1 is classified as a highly dangerous cause of cancer in the international classification. Conversely, the congenital POLD1 / 2 mutations described in the study lead to a reduced intrinsic activity (the "actual task") of the polymerase δ and possibly increases the chances of developing cancer at an earlier age (cancer predisposition syndrome). The present study also aims to bring awareness into the research and help identify additional patients for a systematic analysis of the cancer risk in affected children and children with related illnesses.

The Study: 

"Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress” was published in the Journal of Clinical Investigation on 26 August 2019, DOI: 10.1172/JCI128903

Authors: Cecilia Domínguez Conde*, Özlem Yüce Petronczki*, Safa Baris*, Katharina L. Willmann*, Enrico Girardi, Elisabeth Salzer, Stefan Weitzer, Rico Chandra Ardy, Ana Krolo, Hanna Ijspeert, Ayca Kiykim, Elif Karakoc-Aydiner, Elisabeth Förster-Waldl, Leo Kager, Winfried F. Pickl, Giulio Superti-Furga, Javier Martínez, Joanna I. Loizou, Ahmet Ozen, Mirjam van der Burg, and Kaan Boztug

Funding: The study was funded by the European Research Council (ERC) under the European Union Seventh Framework Program (FP7/2007-2013; ERC grant agreement 310857, to KB), Austrian National Bank (ÖNB Jubilee Fund 16385, to KB), a grant from the Jeffrey Modell Foundation (to KB and MB), and the Austrian Science Fund Lise Meitner Program Fellowship (FWF M1809, to KLW).