UNLABELLED: Mutations in the Fas gene (TNFRSF6) are the most common causes of Autoimmune Lymphoproliferative Syndrome (ALPS-FAS). PURPOSE: 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.
UNLABELLED: Mutations in the Fas gene (TNFRSF6) are the most common causes of Autoimmune Lymphoproliferative Syndrome (ALPS-FAS). PURPOSE: 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-C107Ypatients 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: Joao B Oliveira; Jack J Bleesing; Umberto Dianzani; Thomas A Fleisher; Elaine S Jaffe; Michael J Lenardo; Frederic Rieux-Laucat; Richard M Siegel; Helen C Su; David T Teachey; V Koneti Rao Journal: Blood Date: 2010-06-10 Impact factor: 22.113
Authors: G H Fisher; F J Rosenberg; S E Straus; J K Dale; L A Middleton; A Y Lin; W Strober; M J Lenardo; J M Puck Journal: Cell Date: 1995-06-16 Impact factor: 41.582
Authors: S T Ju; D J Panka; H Cui; R Ettinger; M el-Khatib; D H Sherr; B Z Stanger; A Marshak-Rothstein Journal: Nature Date: 1995-02-02 Impact factor: 49.962
Authors: J Yancoski; C Rocco; A Bernasconi; M Oleastro; L Bezrodnik; C Vrátnica; F Haerynck; S D Rosenzweig Journal: Infect Genet Evol Date: 2009-03-09 Impact factor: 3.342
Authors: A Bettinardi; D Brugnoni; E Quiròs-Roldan; A Malagoli; S La Grutta; A Correra; L D Notarangelo Journal: Blood Date: 1997-02-01 Impact factor: 22.113