A previously unknown gene mutation revealed the role of a key molecule for immune cell development. An international team of scientists led by Kaan Boztug from CeMM Research Institute for Molecular Medicine of the Austrian Academy of Sciences, the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases and the Medical University at Vienna gained fundamentally new insights into the human immune system by studying this newly discovered mutation. Moreover, their research revealed a potential personalized therapy for this rare disease. The study, published in Nature Immunology, clearly highlights the importance and opportunities of research in the field of rare diseases.
A twelve-year old patient was the starting point of the study: Since his birth, the child suffered from severe, life-threatening infections. Immunological analyses showed a disturbed ratio of white blood cells, the so-called lymphocytes, hampering his immune system to fight efficiently against invading pathogens. Three of his six siblings died within the first two years of life, presumably due to similar complications. Although the origin of their condition was unknown, the researchers assumed a genetic trait in four severely diseased children of the same family.
To investigate rare patients like these, the new Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) was founded in Vienna. In collaboration with CeMM, the Medical University Vienna and the St. Anna Children's Cancer Research Institute, LBI-RUD was established by the Ludwig Boltzmann Gesellschaft in April 2016. “The accumulated expertise of our institute is unique” states Kaan Boztug, Director of the LBI-RUD and head of the study. “We are the ideal place to find the molecular cause of rare – and most often genetic – diseases, and to develop this knowledge into targeted therapies”.
“Our analyses of the patient’s and his parents’ genomes indeed confirmed that the boy’s disorder had a genetic cause”, explains Elisabeth Salzer, postdoctoral fellow at CeMM and first author of the study. Using next generation sequencing – a modern and hi ghly efficient genetic method to detect disease- causing mutations – the researchers found an error in the gene encoding RASPGR1, a key protein for the development of lymphocytes. The healthy parents, as well as the three healthy siblings, only had one copy of the mutation in their genome, while the diseased boy had inherited both faulty copies from his parents.
Until this time, the function of RASGPR1 in the immune system was only partially studied in rodent models. Its role in humans was unknown, and a mutation that inhibited the protein had never been reported. The case of the 12-year old patient not only showed that the lack of RASGPR1 impairs T lymphocytes, but also that the protein plays a so far unknown role for maintaining the cellular scaffold (cytoskeleton) in natural killer (NK-) cells. Through a series of further experiments, the researchers were able to analyze the faulty molecular circuits in greater detail. Eventually, the scientist even found an approved drug, lenalidomide, that has the potential to reverse some effects of the newly discovered RASGRP1 deficiency. Therefore, this study is a prime example for the importance and opportunities of studying rare diseases – as it is done at the LBI-RUD: “The whole process from the discovery of a gene defect as cause for a rare disease to the exploration of the disease-causing mechanism to the development of a personalized therapy does much more than helping the affected patients”, explains Kaan Boztug, “Virtually every case – such as the immunodeficiency of this young patient – provides profound new insights into the human organism and paves the way towards a future precision medicine.”