Autoimmune lymphoproliferative syndrome with defective fas: Genotype influences penetrance

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance. Most patients have a heterozygous mutation in the APT1 gene, which encodes Fas (CD95, APO-1), mediator of an apoptotic pathway crucial to lymphocyte homeostasis. Of 17 unique APT1 muta tions in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which enc ode the intracellular portion of Fas. In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-Fas agonis t monoclonal antibody. Similar defects were found in a Fas-negative cell li ne transfected with cDNAs bearing each of the mutations. In cotransfection experiments, Fas constructs with either intra- or extracellular mutations c aused dominant inhibition of apoptosis mediated by wild-type Fas. Two misse nse Fas variants, not restricted to patients with ALPS, were identified. Va riant A(-1)T at the Fas signal-sequence:cleavage site, which mediates;apopt osis less well than wild-type Fas and is partially inhibitory, was present in 13% of African American alleles. Among the ALPS-associated Eas mutants, dominant inhibition of apoptosis was much more pronounced in mutants affect ing the intracellular, versus extracellular, portion of the Fas receptor. M utations causing disruption of the intracellular Fas death domain also show ed a higher penetrance of ALPS phenotype features in mutation-bearing relat ives. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutation s. Thus, the location of mutations within APT1 strongly influences the deve lopment and the severity of ALPS.