title: A missense mutation in the extracellular domain of Fas: the most common change in Argentinean patients with autoimmune lymphoproliferative syndrome represents a founder effect.
abstract: Mutations in the Fas gene (TNFRSF6) are the most common causes of Autoimmune Lymphoproliferative Syndrome (ALPS-FAS).
  
  
  OBJECTIVE
  In Argentina almost a third of patients with ALPS-FAS present a missense mutation affecting the extracellular cysteine rich domain 2 of Fas, p.Cys107Tyr (C107Y). This change was found in homozygous state in 2 patients from a consanguineous family, and heterozygously, in 3 other patients from 3 unrelated families. In these families, 12 relatives were identified as healthy carriers of the mutation. We sought to test the hypothesis that this mutation actually represents a single haplotype of TNFRSF6.
  
  
  METHODS
  DNAs from ALPS-C107Y patients and their families, as well as from 150 Argentinean control subjects were sequenced for the known higher frequency single nucleotide polymorphisms (SNPs) of TNFRSF6. The C107Y-carriers were also genotyped at 5 microsatellites proximal to the Fas gene locus.
  
  
  RESULTS
  All C107Y alleles presented a unique intragenic haplotype that could be restricted to this group. Extent of haplotype sharing and variability of microsatellite alleles in C107Y chromosomes support the presence of a single haplotype block including the mutation and encompassing 2.395 Mb.
  
  
  CONCLUSIONS
  A founder effect for C107Y has been evidenced in this work and the most common recent ancestor to the patients probably lived 350 years ago. This constitutes the first report of a founder event in ALPS.
authors: Servicio de Inmunología y Reumatología, Hospital de Pediatría J. P. Garrahan, Buenos Aires, Argentina.
authors: María Gabriela
authors: MG
authors: Simesen de Bielke
authors: Judith
authors: J
authors: Yancoski
authors: Carlos
authors: C
authors: Rocco
authors: Laura E
authors: LE
authors: Pérez
authors: Claudio
authors: C
authors: Cantisano
authors: Néstor
authors: N
authors: Pérez
authors: Matías
authors: M
authors: Oleastro
authors: Silvia
authors: S
authors: Danielian
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001118:Argentina; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D019014:fas Receptor / Q000235:genetics*
chemical_list: C491901:FAS protein, human; D019014:fas Receptor