Grants Awarded

The use of a newly generated murine model to determine the broad role of STXBP2 in FHL5 pathogenesis

Principal Investigator
Fernando Sepulveda, Ph.D.
Imagine Institute
Paris, France

Date of Award

December 2016

Amount of Award

Layperson Summary
The understanding of the molecular and cellular events leading to the occurrence of HLH is critical for the design of less toxic and more targeted therapies to treat this otherwise life-threatening syndrome. Studies of animal models of HLH have contributed to our understanding of the link between the genetic defects of the cytotoxic machinery and the aberrant immune balance observed in HLH patients. The goal of this proposal is to further dissect the precise mechanisms responsible for the broad clinical spectrum of manifestations encountered in patients bearing mutations in the STXBP2 gene, which account for a familial form of HLH (FHL5). FHL5 patients experience gastrointestinal symptoms manifesting with early and severe, protracted diarrhea besides the impaired capacity to eliminate viral infections or to fight against tumors. In the panel of unusual clinical features, encountered in some FHL5 patients, are also included sensorineural hearing loss documented in some patients, hypogammaglobulinemia, bleeding tendency andrenal tubular dysfunction. Hence, we generated a unique and relevant mouse model to elucidate the causes of these dysregulations. Given the variable clinical manifestations of FHL5 patients that go beyond the classical impaired cytotoxic activity, a hallmark of familial forms of HLH, we will address the possible contribution of other cells types in HLH pathogenesis. More specifically, we will investigate the roleof STXBP2 in antigen-presenting cells and epithelial cells. Impairment of the main functions of both hematopoietic and nonhematopoietic cells may contribute to FHL5 manifestations in the absence of STXBP2 protein. Altogether, we are positive that this project will increase our understanding of the consequences of STXBP2 deficiency in relevant cell types, leading to significantly improve the diagnosis, identification of possible complications and hopefully to the development of more efficient therapies for FHL5 patients.