Centre de Référence des Pathologies Plaquettaires, Plateforme Technologique d'Innovation Biomédicale, Hôpital Xavier Arnozan, Pessac, France.
Eur J Hum Genet. 2011 Sep;19(9):981-7. doi: 10.1038/ejhg.2011.61. Epub 2011 Apr 13.
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.
该 c.1544+1G>A 取代在 5' 剪接供体位点的内含子 15 的 ITGA2B 基因，称为法国吉普赛突变，导致 Glanzmann 血小板无力症，一种遗传性出血性疾病作为常染色体隐性遗传特征和 αIIbβ3 血小板整合素的改变的合成。到目前为止，这种突变只在来自法国吉普赛家庭的受影响个体中发现，强烈提示存在一个奠基者效应。我们的目标是研究法国吉普赛突变的起源。我们通过使用一组患者之间共享单倍型的长度的基于可能性的方法来估计突变的年龄。为此，我们对 23 名 Manouche 血统的个体进行了基因分型；包括 9 名 Glanzmann 血小板无力症患者，纯合子法国吉普赛突变，6 名杂合子携带者和 8 名纯合野生型个体。他们使用高分辨率熔解曲线分析对四个单核苷酸多态性进行基因分型，并且在染色体 17 上的 BRCA1 和 THRA 基因中的两个 CA 重复，使用片段分析凝胶。我们发现，覆盖 4-cM 区域的五个多态性位点的单倍型与法国吉普赛突变强烈相关，提示存在奠基者效应。该奠基突变的估计年龄为 300-400 岁（范围 255-552 岁）。因此，所有 5' 剪接供体位点的 c.1544+1G>A 法国吉普赛突变的携带者都来自 300-400 年前的共同祖先。
