Figure 1.

Genomic structure and common polymorphisms of the human F8. (A) The hg17 sequence used as a reference for F8 spans approximately 286 kb and contains the approximately 186-kb structural locus and 50 kb of contiguous genomic-DNA flanking its 5′ and 3′ ends. F8 consists of 26 exons (red triangles) and 25 introns (black lines). The approximately 1.2 kb of promoter and approximately 0.3 kb of 3′ genomic segments scanned for polymorphisms are indicated. The numerous repetitive elements (RepeatMasker) are indicated by different-colored triangles. (B) The 41 amplicons (amp) generated for variation detection and genotyping are indicated by open boxes. (C) The 47 variants are designated by their M- and m-alleles and position in the F8 TU with respect to its major start site, which is indicated as nt 1 and corresponds to base 465469 in the reverse compliment of NG_005114. Promoter SNPs are located upstream of nt −1, which corresponds to base 465468 in the reverse compliment of NG_005114. The 17 exonic SNPs, which include 11 in coding sequence, are also designated by their nt and amino acid position in the polyadenylated mRNA and mature circulating FVIII protein, respectively. Finally, the 4 ns-SNPs and Trp255Cys, which encode the amino acid substitutions indicated, are shown in green. 53206G>T is denoted by a red asterisk, as it represents a known missense mutation encoding Trp255Cys, which was found originally in a male Chinese patient with mild hemophilia A. In the present study, the minor T-allele (Cys²⁵⁵) was found in an asymptomatic heterozygous SEA female.