title: Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome.
abstract: Autoimmune lymphoproliferative syndrome (ALPS) is characterized by childhood onset of lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, elevated numbers of double-negative T (DNT) cells, and increased risk of lymphoma. Most cases of ALPS are associated with germline mutations of the FAS gene (type Ia), whereas some cases have been noted to have a somatic mutation of FAS primarily in their DNT cells. We sought to determine the proportion of patients with somatic FAS mutations among a group of our ALPS patients with no detectable germline mutation and to further characterize them. We found more than one-third (12 of 31) of the patients tested had somatic FAS mutations, primarily involving the intracellular domain of FAS resulting in loss of normal FAS signaling. Similar to ALPS type Ia patients, the somatic ALPS patients had increased DNT cell numbers and elevated levels of serum vitamin B(12), interleukin-10, and sFAS-L. These data support testing for somatic FAS mutations in DNT cells from ALPS patients with no detectable germline mutation and a similar clinical and laboratory phenotype to that of ALPS type Ia. These findings also highlight the potential role for somatic mutations in the pathogenesis of nonmalignant and/or autoimmune hematologic conditions in adults and children.
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1888, USA. kdowdell@niaid.nih.gov
authors.forename: Kennichi C
authors.initials: KC
authors.lastname: Dowdell
authors.forename: Julie E
authors.initials: JE
authors.lastname: Niemela
authors.forename: Susan
authors.initials: S
authors.lastname: Price
authors.forename: Joie
authors.initials: J
authors.lastname: Davis
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hornung
authors.forename: João Bosco
authors.initials: JB
authors.lastname: Oliveira
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Puck
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Cohen
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: V Koneti
authors.initials: VK
authors.lastname: Rao
mesh_terms: D000328:Adult; D056735:Autoimmune Lymphoproliferative Syndrome / Q000097:blood / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D053222:Fas Ligand Protein / Q000097:blood; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000097:blood; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation; D017434:Protein Structure, Tertiary; D012307:Risk Factors; D014805:Vitamin B 12 / Q000097:blood; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C508609:IL10 protein, human; D019014:fas Receptor; D016753:Interleukin-10; D014805:Vitamin B 12