Grant Awarded in 2017

Unraveling Genetic Mysteries in Hemophagocytic Lymphohistiocytosis

Principal Investigator
Ivan Chinn
Baylor College of Medicine
Houston, TX USA


Date of Award

December 2017

Amount of Award
$50,000

Layperson Summary

Hemophagocytic lymphohistiocytosis (HLH) occurs from extreme, persistent immune activation and is known to have many causes. Some individuals are born with mutations in genes that cause HLH, but not all of these genes are known. Because these possibilities remain undefined, choosing the most appropriate treatment for a patient can be challenging. Thus, an essential need exists for improved understanding of the genetic causes of HLH.

Our goal is to identify new genetic causes of HLH. We believe that over 50% of all HLH patients who lack disease-causing mutations in “familial HLH” genes actually have HLH-producing mutations in other genes. We will use a recently developed technology known as whole exome sequencing (WES) to find these genes in HLH patients. In 50 non-familial HLH subjects tested by this method, likely genetic explanations were found in 27 (54%), including mutations in genes that cause primary immunodeficiency diseases, in genes associated with dysregulated immune activation or proliferation, and in previously unknown gene candidates. In this proposed work, WES will be applied to additional subjects to identify further non-familial HLH gene cases. This project will also establish a program for confirming the effect of mutations found through WES. As an example, we will test mutations discovered from a subject in a potentially new HLH-causing gene, NLRC3. Cas9/CRISPR technology will be used to silence expression of NLRC3 in appropriate cell lines. Copies of NLRC3 containing the mutations will be put back into the cells. The activity of the cells containing the mutated NLRC3 proteins will then be compared to cells that lack NLRC3 expression, cells from the HLH subject, and normal control cells. We expect cells containing mutant NLRC3 to behave similarly to subject cells and to cells that lack NLRC3 expression.

Overall, we expect this work to improve our understanding of genetic causes of HLH and eventually support the use of specific therapies for certain HLH patients in the future. Thus, ultimately, these outcomes are anticipated to have an important positive impact by enhancing the timely diagnosis and management of HLH patients.




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