Faulty gene causes newly discovered human immunodeficiency

The paper, published in the ‘Nature Immunology’ journal, expands on how the research team identified a 12 year-old patient who suffered repeated life-threatening infections since his birth. Three of the patient’s six siblings had died within their first two years seemingly of a similar disorder. The scientists suspected that a genetic condition might be the culprit. ‘Our analyses of the patient’s and his parents’ genomes indeed confirmed that the boy’s disorder had a genetic cause,’ said Dr. Elisabeth Salzer, first author of the paper.

Specifically, the genetic cause is an error in the gene RASGRP1 that renders the gene inactive. This type of mutation had never been reported before, with the healthy parents and healthy siblings carrying one mutated copy of the gene and one normal copy that compensates for the faulty gene. The patient though inherited one mutated copy from each parent.

The patient has a primary immunodeficiency that involves a new combination of immune defects in essential members of the immune system, in particular T cells, B cells and Natural Killer cells. Until now, the role played by RASGRP1 has not been studied in humans.

To determine the mechanisms that might lead to the patient’s inability to fight infections, the IMMUNOCORE team, based in Vienna, Austria, collaborated with the lab of Dr. Jordan Orange at Baylor College of Medicine in Houston, Texas. ‘The clinical characteristics of the patient suggested that some of the defective immune mechanisms of his condition were of the type we study in our lab,’ commented Orange. ‘We applied our expertise on quantitative and high-resolution imaging to study the effects of the RASGRP1 mutation in Natural Killer cells.’

The Baylor group found that RASGRP1 plays a role in dynein functions in Natural Killer cells, with dynein being a motor protein – its function is to move things around inside cells. ‘Like motorised vehicles carrying people around a city, motor proteins such as dynein transport items in cells where they need to go,’ explained Orange. ‘Natural killer cells rely heavily on the dynein transportation system to secrete poisons onto deceased cells, cells infected with viruses for instance, to destroy them. In this diease, the ‘motorised vehicles’ are not working properly; the poison cannot be transported to the virus-infected cells and the patient cannot get rid of infections.’

The studies from the Orange lab provided a functional link between the defects in Natural Killer cells and dynein, which in combination with other observations led the Austrian IMMUNOCORE team to try the drug lenalidomide to treat the patient. Positively, the drug showed the potential to reverse some of the effects of the RASGRP1 mutation.

‘The whole process from the discovery of a gene defect as the cause of a rare disease to the exploration of the disease-causing mechanism to the development of a personalised therapy does much more than helping the affected patients,’ said Dr. Kaan Boztug, senior author of the paper. ‘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.’

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