A UNIQUE HAPLOTYPE OF FAS GENE LINKED TO A FOUNDER MUTATION ASSOCIATED WITH AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME (ALPS) IN ARGENTINA SEEMS TO BE ABSENT IN POPULATIONS WITH AMERINDIAN ETHNIC ANCESTRY

SIMESEN DE BIELKE MG; YANCOSKI J; ROCCO C; PROSPERI N; OLEASTRO M; PÉREZ N; CANTISANO C; BAILLIET G; BRAVI CM; DANIELIAN S

México

Encuentro; II Meeting of Latin American Society for Immunodeficiencies (LASID); 2011

Latin American Society for Immunodeficiencies (LASID)

INTRODUCTION: FAS GENE (TNFRSF6) MUTATIONS ARE THE MOST COMMON CAUSES OF ALPS. WE FOUND A MUTATION IN TNFRSF6 (C107Y) IN TWO HOMOZYGOUS PATIENTS AND IN THREE PATIENTS, IN HETEROZYGOUS STATE. PREVIOUSLY, WE SHOWED THAT C107Y PROBABLY REPRESENTS A FOUNDER EFFECT THAT AROSE APPROXIMATELY 350 YEARS AGO, BY ANALYZING 10 POLYMORPHIC SITES. AMONG THESE SITES, SIX INTRAGENICS SNPS REVEALED A DISTINCTIVE HAPLOTYPE (GTATCC) SEGREGATING WITH C107Y, NOT DETECTED ON 200 CHROMOSOMES FROM OUR HEALTHY GROUP, NOR IN A PREVIOUS REPORT ON 150 CAUCASIANS. TAKING INTO ACCOUNT THE OVERREPRESENTATION OF C107Y ASSOCIATED WITH GTATCC IN ARGENTINA, WE UNDERTOOK A LARGE STUDY ON NATIVE ARGENTINEAN POPULATIONS TO TEST RESTRICTION OF GTATCC TO A PARTICULAR ETHNIC GROUP. METHODS: WE STUDIED 324 SAMPLES FROM NORTH ARGENTINEAN POPULATIONS WHICH HAVE MORE THAN 80% OF AMERINDIANS HAPLOGROUPS IN MITOCHONDRIAL DNA. THE SNP C.528(+46)C>T WAS ANALYZED BY RESTRICTION FRAGMENT LENGTH POLYMORPHISM (RFLP). THE OTHER SNPS (-1377G>A, -691T>C, -671A>G, C.699(+82)C>G, C.836C>T) WERE STUDIED BY PCR AND SEQUENCING. FOR SOME SAMPLES CLONING IN BACTERIA WAS PERFORMED BUT, DUE TO THE DISTANCE BETWEEN SEVERAL SNPS SOME UNPHASED HAPLOTYPES PAIRS REMAINED UNDETERMINED. RESULTS: FIRSTLY, SCREENING FOR THE MINOR ALLELE T OF THE SNP C.528(+46)C>T ASSOCIATED WITH THE HAPLOTYPE ALLOWED US TO DISCARD 176 SAMPLES. THIS ALLELE WAS FOUND IN HIGHER FREQUENCY IN AMERINDIAN GROUPS (MEAN VALUE: 26.54%) COMPARED TO CAUCASIANS (10.3%). IN THE RESTING 148 SAMPLES WHICH ARE C/T OR T/T IN THIS SNP, WE EVALUATED SNPS FROM THE PROMOTER REGION REJECTING 61 SAMPLES. FINALLY TWO OTHER SNPS GAVE US 45 PROBABLY SAMPLES WITH GTATCC. THE LATTER WERE UNPHASED HAPLOTYPE PAIRS. A SIGNIFICANT NUMBER OF THEM COULD BE REJECTED BY CLONING. IN ADDITION, FURTHER ANALYSIS WITH OUR DATA SUGGEST THAT THE EXPECT FREQUENCY TO FIND GTATCC IS VERY LOW. ACTUALLY, GIVEN THAT THE NUMBER OF UNIQUE HAPLOTYPES IN T/T SAMPLES CONSIDERING SNP 528, IS LESS THAN 2,1% (1/48 ALELLES) AND THAT THE NUMBER OF HAPLOTYPES UNDETERMINED IS 13%, THE EXPECTED FREQUENCY TO FIND GTATCC IS LESS THAN 2,6%. CONCLUSIONS: THE SNP C.528 COULD REFLECT ETHNIC DIFFERENCES: THE MINOR ALLELE OCCURRED AT A HIGHER FREQUENCY IN AMERINDIANS COMPARED TO CAUCASIANS, BUT ALSO IN AFRICAN AMERICAN INDIVIDUALS (25.50%) BY A PREVIOUS REPORT. INDEED, THE MUTATION C107Y WAS RECENTLY REPORTED IN A PATIENT WITH AFRICAN ORIGIN.