REDUCED TYK2 SHP-1 INTERACTION AND LACK OF SHP-1 MUTATION IN A KINDRED OF FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS/

Familial hemophagocytic lymphohistiocytosis (FHLH) is an autosomal rec essive disease with features similar to those of the murine motheaten phenotype resulting from mutations of protein tyrosine phosphatase SHP -1. This has raised the possibility that defects in SHP-1 or SHP-1-reg ulated signaling molecules may be present in FHLH. In this study, we e xamined SHP-1 protein and transcript in the peripheral blood mononucle ar cells (PBMC) of an FHLH family. Our results show that the FHLH pati ent and the parents express comparable levels of a single SHP-1 protei n and that the SHP-1 cDNA clone from the patient contains no mutation in the coding region. Interestingly, a reduced association of SHP-1 wi th the Jak family kinase Tyk2 was detected in the patient and the defe ct appears to have been inherited from one of the parents. This reduce d SHP-1/Tyk2 association is likely due to a defect in Tyk2 or in cellu lar factors regulating Tyk2, because we found no abnormalities in SHP- 1 or in SHP-1 association with the other Jak kinases. These data demon strate that the SHP-1 gene is intact in FHLH and that the defect in so me cases with this disease may involve signaling molecules regulated b y SHP-1.