title: Somatic loss of heterozygosity, but not haploinsufficiency alone, leads to full-blown autoimmune lymphoproliferative syndrome in 1 of 12 family members with FAS start codon mutation.
abstract: We describe a family with 12 members carrying a heterozygous germline FAS c.3G>T start codon mutation leading to FAS haploinsufficiency. One patient had autoimmune lymphoproliferative syndrome (ALPS), one had recovered from ALPS, and ten mutation-positive relatives (MPRs) were healthy. FAS-mediated apoptosis and surface expression of FAS in single-positive T cells were lower for MPRs but did not discriminate between them and the ALPS patient. However, double-negative (DN) T cells of the ALPS patient had no FAS expression due to somatic loss of heterozygosity. Our results in this kindred suggest that FAS haploinsufficiency does not cause ALPS-FAS, but that modifying genetic events are crucial for its pathogenesis. FAS surface expression on DN T cells should be assessed routinely and FAS haploinsufficient patients should be followed as its potential for lymphomagenesis is not well defined and a second hit might occur later on.
authors.affiliation: INSERM U768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Hôpital Necker-Enfants Malades, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Section of Immunology, University Children's Hospital Carl-Gustav Carus, Dresden, Germany. Electronic address: fabian.hauck@med.uni-muenchen.de.
authors.forename: Fabian
authors.initials: F
authors.lastname: Hauck
authors.affiliation: INSERM U768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Hôpital Necker-Enfants Malades, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: aude.magerus@inserm.fr.
authors.forename: Aude
authors.initials: A
authors.lastname: Magerus-Chatinet
authors.affiliation: Laboratoire de Biochimie Générale, Hôpital Necker-Enfants Malades, Paris, France. Electronic address: stephanie.vicca@nck.aphp.fr.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Vicca
authors.affiliation: Centre of Chronic Immunodeficiency, University Medical Centre, Freiburg, Germany. Electronic address: anne.rensing-ehl@uniklinik-freiburg.de.
authors.forename: Anne
authors.initials: A
authors.lastname: Rensing-Ehl
authors.affiliation: Section of Immunology, University Children's Hospital Carl-Gustav Carus, Dresden, Germany. Electronic address: angela.roesen-wolff@uniklinikum-dresden.de.
authors.forename: Angela
authors.initials: A
authors.lastname: Roesen-Wolff
authors.affiliation: Section of Immunology, University Children's Hospital Carl-Gustav Carus, Dresden, Germany. Electronic address: joachim.roesler@uniklinikum-dresden.de.
authors.forename: Joachim
authors.initials: J
authors.lastname: Roesler
authors.affiliation: INSERM U768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Hôpital Necker-Enfants Malades, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: frederic.rieux-laucat@inserm.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rieux-Laucat
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000235:genetics; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics*; D001483:Base Sequence; D002478:Cells, Cultured; D018387:Codon, Initiator / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005434:Flow Cytometry; D057895:Haploinsufficiency; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D055815:Young Adult; D019014:fas Receptor / Q000235:genetics*
chemical_list: D018387:Codon, Initiator; D019014:fas Receptor