A unique haplotype of FAS gene linked to a founder mutation is restricted to a particular ethnic group?

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

Buenos Aires

Jornada; First French Argentine Immunology Congress (FAIC)/ LVIII Reunión Anual de la Sociedad Argentina de Inmunología \3º Jornadas Argentinas de Inmunodeficiencias Primarias (SAP); 2010

Sociedad Argentina de Inmunología \ French Society of Immunology

Mutations of the FAS gene (TNFRSF6) are the most common causes of Autoimmune lymphoproliferative Syndrome (ALPS), and the majority of them affects the intracellular region. We found a novel mutation in exon 3 of TNFRSF6, in two patients from a consanguineous family, presented in homozygous state. This mutation changes a cytosine for a tyrosine (C91Y) in one of the conservative domain of the extracellular region, cysteine rich domain 2 (CRD2). Interestingly, this particular change was found in three other patients from three unrelated families, in heterozygous state. To determine whether C91Y represents a DNA mutational hotspot or a founder effect, 10 polymorphic sites on chromosome 10 were analyzed: 6 intragenic TNFRSF6 single nucleotide polymorphisms (SNPs) with minor allele frequencies ≥ 5% and 5 extragenic microsatellites surrounding this gene. The six intragenic SNPs revealed a distinctive haplotype (GTATCC) which segregated with C91Y mutation and was not detected on 100 control chromosomes. All these SNPs are highly polymorphic and we found the ancestral allele in all of them except for c.528 (+46) C>T. These data strongly suggest that the C91Y mutated allele originated from a single founder. We applied a modified likelihood´based method to estimate the age of the most recent common ancestor carrying mutation C91Y. Extent of haplotype sharing and variability of microsatellite alleles in C91Y chromosomes suggest that this mutation arose approximately 350 years ago. Taking into account that GTATCC haplotype was not found in our control group nor in a previous report on 150 Caucausian subjects from USA, we have undertaken a large study on Native American Argentinean populations, to test if the unique haplotype carrying this novel mutation is restricted to a particular ethnic group. For instance, the SNP c.528 (+46) C>T could reflect ethnic differences since the minor allele T occurred at a higher frequency in Amerindians (26.3%) compared to Caucasians (10.3%).