The genetic cause and biological mechanisms linked to a new
human immunodeficiency has been discovered by multi-institutional, international team of scientists. The study, which is published in Nature Immunology, also identifies a potential treatment.
Dr. Kaan Boztug, who is the senior author of the paper and an
investigator at the 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, led
the team of dozens of scientists from various institutions across the
world, including Baylor College of Medicine.
‘The gene RASGRP1 plays a role in dynein functions in Natural Killer cells. An error in RASGRP1 renders the gene inactive and has been linked to a new human immunodeficiency.’
First author Dr. Elisabeth Salzer, postdoctoral fellow in the
Boztug lab, 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 researchers suspected that a genetic condition might be
linked to the patient's inability to fight infection.
"Our analyses of the patient's and his parents' genomes indeed
confirmed that the boy's disorder had a genetic cause," said Salzer.
The genetic cause is an error in the gene RASGRP1 that renders
the gene inactive. This type of mutation had never been reported before.
The healthy parents and the healthy siblings carry one mutated copy of
the gene and one normal copy that compensates for the faulty gene. The
patient, on the other hand, inherited one mutated copy from each parent.
The patient presented with a primary immunodeficiency that
involves a new combination of immune defects in essential members of the
immune system, T cells, B cells and Natural Killer cells. Until now,
the role RASGRP1 plays in the immune system had not been studied in
To determine the mechanisms that might lead to the patient's
inability to fight infections, the Vienna group collaborated with the
lab of Dr. Jordan Orange at Baylor. Orange is professor and section head
for immunology, allergy and rheumatology in pediatrics at Baylor and
the director of the Center for Human Immunobiology at Texas Children's
"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," said 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 the gene RASGRP1 plays a role in
dynein functions in Natural Killer cells. Dynein is a motor protein; it
moves things around inside cells.
"Like motorized vehicles carrying people around a city, motor
proteins such as dynein transport items inside cells where they need to
go," said Orange. "Natural Killer cells rely heavily on the dynein
transportation system to secrete poisons onto diseased cells - cells
infected with viruses, for instance - to destroy them. In this disease,
the 'motorized vehicles' are not working properly; the poison cannot be
transported to the virus-infected cells and the patient cannot get rid
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 team to try the
drug lenalidomide to treat the patient. The drug showed potential to
reverse some of the effects of RASGRP1's 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 personalized therapy does much more
than helping the affected patients," said Boztug. "Virtually every case -
such as the immunodeficiency of this young patient - provides profound
new insights into the human organism and paves the way toward a future
"This work was the result of a tremendous collaboration among
international groups of researchers and with the family of the patient,"
said Orange. "Our work at Baylor and Texas Children's Hospital
continues to include us among the world leaders in the study of primary
immnodeficiencies and their biological underpinnings."