title: Haploinsufficiency, rather than the effect of an excessive production of soluble CD95 (CD95{Delta}TM), is the basis for ALPS Ia in a family with duplicated 3' splice site AG in CD95 intron 5 on one allele.
abstract: Autoimmune lymphoproliferative syndrome type Ia (ALPS Ia) is caused by mutations in the CD95/APO1/FAS (TN-FRSF6) gene, which lead to a defective CD95 ligand (CD95L)-induced apoptosis. Soluble CD95 (sCD95) has been suggested to play an important role in the pathogenesis of diverse autoimmune and malignant diseases by antagonizing CD95L. Here we evaluate a family with 4 of its 5 members harboring an ex-6-3C-->G mutation that affects the splice cis regulatory region (cctacag/ex-6-->cctagag/ex-6) of the CD95 gene. The mutation causes skipping of exon-6, which encodes the transmembrane region of CD95, and thereby leads to an excessive production of sCD95 in all 4 affected individuals. The mutation is associated with a low penetrance of disease phenotype and caused mild and transient ALPS in one male patient whereas all other family members are completely healthy. In all family members with the mutation we found that the cell surface expression of CD95 was low and the activated T cells were resistant to CD95-induced apoptosis. Unexpectedly, excessive production or addition of sCD95 had no effect on the CD95-induced apoptosis in diverse cells. In contrast, increasing the surface expression of CD95 was able to correct the defect in apoptosis. Thus we conclude that the ALPS in the one male patient was caused by haploinsufficiency of membrane CD95 expression. Our data challenge the hypothesis that sCD95 causes autoimmunity.
authors.affiliation: Department of Pediatrics, University Clinic Carl Gustav Carus, Fetscherstr 74, 01307 Dresden, Germany. roeslerj@res.urz.tu-dresden.de
authors.forename: Joachim
authors.initials: J
authors.lastname: Roesler
authors.forename: Jose-Maria
authors.initials: JM
authors.lastname: Izquierdo
authors.forename: Martin
authors.initials: M
authors.lastname: Ryser
authors.forename: Angela
authors.initials: A
authors.lastname: Rösen-Wolff
authors.forename: Manfred
authors.initials: M
authors.lastname: Gahr
authors.forename: Juan
authors.initials: J
authors.lastname: Valcarcel
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
authors.forename: Lixin
authors.initials: L
authors.lastname: Zheng
mesh_terms: D000227:Adenine Nucleotides / Q000235:genetics; D000483:Alleles; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D002648:Child; D006150:Guanine Nucleotides / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology; D008297:Male; D009154:Mutation; D010641:Phenotype; D012326:RNA Splicing; D019014:fas Receptor / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology
chemical_list: D000227:Adenine Nucleotides; D006150:Guanine Nucleotides; D019014:fas Receptor