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Homozygozity Mapping for Identification of a Novel Genetic Defect in Patients with Familial Hemphogocytic Lymphohistiocytosis
Principal Investigator
Udo zur Stadt MD
University Medical Center Hamburg Eppendorf – Hamburg, Germany
Date of Award
September 2006
Amount of Award
$44,100
Layperson Summary
Despite the fact that FHL is a very rare disease, the identification of underlying mutations is highly relevant since affected persons have a usually fatal outcome if the disease is not correctly diagnosed and if appropriate therapy is not initiated rapidly. Therefore, the identification of several disease causing mutations has substantially improved the exact diagnosis and treatment modalities such as stem cell transplantation in individual patients. Starting with the identification of mutations in perforin 1, as a key player in cytotoxic death, in 1999, it has become clear that causative FHL genes are involved in pathways affecting cell types that directly take part in the defense against pathogens. Although the cell biological picture of activated macrophages and a reduced cytotoxic answer to infections could contribute to understanding these defects, first evidence was given only after underlying genetic defects have been clarified in different subsets of the disease. The fact that perforin 1 is directly involved in the killing machinery of cytotoxic cells, and the fact that hMunc13-4 delivers such molecules through cytotoxic granules to the plasma membrane of immune cells, allowed the identification of exact mechanisms of viral defense.
The identification of (a) novel genetic subtype(s) will further improve our understanding of these pathways, thus allowing to clarify the etiology of the disease, and make it clear how the respective genetic basis of this heterogeneous disease establishes the clinical phenotype. Furthermore, identification of a gene defect will differentiate the more lethal familial (primary) form from secondary cases that often present with a milder clinical phenotype. Whereas in familial cases a peripheral blood stem cell transplantation is absolutely required, the latter one can be cured with standard chemo-immunotherapy protocols.