Founder effect and estimation of the age of the French Gypsy mutation associated with Glanzmann thrombasthenia in Manouche families

Abstract

The c.1544+1G>A substitution at the 5' splice donor site of intron 15 of the ITGA2B gene, called the French Gypsy mutation, causes Glanzmann thrombasthenia, an inherited hemorrhagic disorder transmitted as an autosomal recessive trait and characterized by an altered synthesis of the platelet αIIbβ3 integrin. So far, this mutation has only been found in affected individuals originating from French Manouche families, strongly suggesting a founder effect. Our goal was to investigate the origin of the French Gypsy mutation. We estimated the age of the mutation by a likelihood-based method that uses the length of the shared haplotypes among a set of patients. For this, we genotyped 23 individuals of Manouche origin; consisting of 9 Glanzmann thrombasthenia patients homozygous for the French Gypsy mutation, 6 heterozygous carriers and 8 homozygous wild-type individuals. They were genotyped for four single-nucleotide polymorphisms using high-resolution melting curve analysis, and for two CA repeats in the BRCA1 and THRA genes at chromosome 17, using fragment analysis gels. We found that a haplotype of five polymorphic loci covering a 4-cM region was strongly associated with the French Gypsy mutation, suggesting a founder effect. The estimated age of this founder mutation was 300-400 years (range 255-552 years). Thus, all carriers of the French Gypsy mutation c.1544+1G>A at intron 15 descended from a common ancestor 300-400 years ago.

Figure 1

c.1544+1G>A mutation affects the splicing and expression of αIIb. (a) Schematic representation of the exon 15/intron 15 boundary of the ITGA2B gene showing the position of the c.1544+1G>A mutation (marked by red lines); (b) mRNA sequence showing the splice products. Eight base pair deletion causes a frameshift, which results in premature stop codon.

Figure 2

Pedigrees of studied cases of GT. Homozygous GT subjects are represented by solid squares or circles; heterozygous individuals by solid squares or circles within open frames. The bars represent the haplotype constructed from four SNPs and two STRs around the French Gypsy mutation of the ITGA2B gene.

Figure 3

Origin of the French Gypsy mutation. Origin of Gypsies , European migration in Balkans , migration in Germany , introduction of the French Gypsy mutation in France and founder effect .