Garvan Scientists Identify Cellular “Glitches” Behind Rare Genetic Disorder

Scientists at the Garvan Institute of Medical Research have identified cellular "glitches" underlying PI3K Delta syndrome 2 (APDS2), a rare genetic disorder caused by alterations to the PI3K protein, resulting in fautly immune cell signaling. PI3K has been shown to play a crucial role in activating immune cells for growth, proliferation, survival, migration, and function. The researchers found that the genetic variations in APDS2 and a similar disorder, APDS1, alter PI3K signaling, leading to distinct downstream effects on the immune system.

Associate Professor Elissa Deenick, Head of the Lymphocyte Signaling and Activation Lab and co-Lead of the Precision Immunology Program at Garvan, says that "This study tells us how signaling in the immune system needs to be tightly balanced to make an effective response to infection."

While these APDS disorders have similar impacts on patients, they follow different genetic pathways. Variations in the PIK3R1 gene underlie APDS2, while variations in PIK3CD underlie APDS1. Though both result in increased PI3K signaling, their subtle differences yield distinct immune effects. For example, in APDS2, fewer responding B cells are generated in response to vaccination, whereas in APDS1, the number of T cells is reduced. Both disorders result in poor antibody responses.

Dr. Tina Nguyen, co-lead author of the study and Research Officer at Garvan, says "Even for people who don’t have these two rare genetic conditions, other genes can impact these pathways – which could contribute to why different people have varied responses to vaccinations."

The findings can help us uncover these molecular processes and develop more targeted therapies for these disorders. "Knowing the genetic basis of a disease can enable targeted, personalized treatment plans that give patients the best chance of effective management or, hopefully over time, a cure," says Professor Stuart Tangye, Head of the Immunobiology and Immunodeficiency Lab at Garvan.

For future work, the researchers plan to track individual responses to treatment and develop blood tests to monitor immune health and dysfunction to give the right drug, at the right dose, at the right time. The study was published in the Journal of Experimental Medicine.