Grants Awarded

Revisiting the Candidate Regions for Familial Hemophagocytic Lymphohistiocytosis (FHLH): Loss-of-Function-Screening Search for the Missing Disease Causing Genes

Principal Investigator
Janos Sumegi MD, PhD
Cincinnati Children’s Hospital Medical Center – Cincinnati, Ohio USA

Date of Award
September 2008

Amount of Award

Layperson Summary
Familial Hemophagocytic Lymphohistiocytosis (FHLH) is almost universally fatal unless aggressively treated soon after diagnosis, and corrected with allogeneic bone marrow transplantation.  All forms of FHLH likely result from genetic defects in the natural down regulating mechanisms of immune/inflammatory responses. Three autosomal recessive gene defects underlie 40-50% of primary (familial) cases worldwide: perforin (20-30%), the major immune cytotoxic protein, MUNC 13-4 (20%), a protein involved in exocytosis of perforin-bearing cytotoxic granules during apoptosis and STX11.  Thus in more than half of the FHLH cases, the affected individuals have other as yet unknown genetic alterations. The classic genetic approach to identify these genes, through linkage analysis, has limitations because linkage analysis requires DNA from relatively large numbers of affected and unaffected members of a single family. Such families are unusual in North America. We estimate at least six or seven genes could be responsible to the various genetic forms of FHLH. In this study, we propose a cell-biology-based approach to accelerate the dissection of FHLH susceptibility loci.  Our strategy utilizes RNA interference, the process where double-stranded RNA induces the homology-dependent degradation of cognate mRNA.  The RNAi strategy will be used to identify candidate genes in lymphohistiocytosis susceptibility regions on chromosomes 9q21.3-22, 11q25, and 14q24-31.