Autoimmune lymphoproliferative syndrome (ALPS) is characterized by
lymphadenopathy, elevated numbers of T cells with alphabeta-
T cell receptors but neither CD4 nor CD8 co-receptors, and impaired lymphocyte apoptosis in vitro. Defects in the
Fas receptor are the most common cause of ALPS (ALPS Ia), but in rare cases other apoptosis
proteins have been implicated, including
caspase-10 (ALPS II). We investigated the role of variants of
caspase-10 in ALPS. Of 32 unrelated probands with ALPS who did not have Fas defects, two were heterozygous for the
caspase-10 missense mutation I406L. Like the previously reported ALPS II-associated mutation L285F, I406L impaired apoptosis when transfected alone and dominantly inhibited apoptosis mediated by wild type
caspase-10 in a co-transfection assay. Other variants in
caspase-10, V410I and Y446C, were found in 3.4 and 1.6% of chromosomes in Caucasians, and in 0.5 and <0.5% of African Americans, respectively. In contrast to L285F and I406L, these variants had no dominant negative effect in co-transfection assays into the H9 lymphocytic cell line. We found healthy individuals homozygous for V410I, challenging the earlier suggestion that homozygosity for V410I alone causes ALPS. Moreover, an association analysis suggested protection from severe disease by
caspase-10 V410I in 63 families with ALPS Ia due to dominant Fas mutations (P<0.05). Thus, different genetic variations in
caspase-10 can produce contrasting phenotypic effects.