[HTML][HTML] The molecular basis for apoptotic defects in patients with CD95 (Fas/Apo-1) mutations

AK Vaishnaw, JR Orlinick, JL Chu… - The Journal of …, 1999 - Am Soc Clin Investig
AK Vaishnaw, JR Orlinick, JL Chu, PH Krammer, MV Chao, KB Elkon
The Journal of clinical investigation, 1999Am Soc Clin Investig
Heterozygous mutations of the receptor CD95 (Fas/Apo-1) are associated with defective
lymphocyte apoptosis and a clinical disease characterized by lymphadenopathy,
splenomegaly, and systemic autoimmunity. From our cohort of 11 families, we studied eight
patients to define the mechanisms responsible for defective CD95-mediated apoptosis.
Mutations in and around the death domain of CD95 had a dominant–negative effect that was
explained by interference with the recruitment of the signal adapter protein, FADD, to the …
Heterozygous mutations of the receptor CD95 (Fas/Apo-1) are associated with defective lymphocyte apoptosis and a clinical disease characterized by lymphadenopathy, splenomegaly, and systemic autoimmunity. From our cohort of 11 families, we studied eight patients to define the mechanisms responsible for defective CD95-mediated apoptosis. Mutations in and around the death domain of CD95 had a dominant–negative effect that was explained by interference with the recruitment of the signal adapter protein, FADD, to the death domain. The intracellular domain (ICD) mutations were associated with a highly penetrant Canale-Smith syndrome (CSS) phenotype and an autosomal dominant inheritance pattern. In contrast, mutations affecting the CD95 extracellular domain (ECD) resulted in failure of extracellular expression of the mutant protein or impaired binding to CD95 ligand. They did not have a dominant–negative effect. In each of the families with an ECD mutation, only a single individual was affected. These observations were consistent with differing mechanisms of action and modes of inheritance of ICD and ECD mutations, suggesting that individuals with an ECD mutation may require additional defect(s) for expression of CSS.
The Journal of Clinical Investigation