Portada Simposios - Supplements - Haematologica

XLII Reunión Nacional de la AEHH y XVI Congreso de la SETH. Simposios
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Figure 1. Genomic organization of factor VIII gene.
Figure 2. Factor IX: from DNA to mature protein.
diagnosis in order to provide improved support to
patients and their families.
The genetic basis of Hemophilia A and B
Mutations in the coagulation factor VIII (FVIII) gene
result in the X-linked recessive bleeding disorder Hemophilia
A, which affects approximately 1 in
5,000 males and very rarely females. The human factor
VIII gene, located at Xq28, consists of twenty-six
exons and is approximately 196 kb in length (fig. 1).
This gene is transcribed into an mRNA of about 9 kb
that codes for a protein with a mature form of
2332 amino acids that circulates in blood associated
to the von Willebrand factor (vWF). A wide range of
gene defects that may result in the absence of functional
FVIII are known, including gross gene deletions
or rearrangements, stop codons and missense mutations.
Missense mutations can also result in impaired
secretion, reduced vWF binding or defective activation
of FVIII. More than 500 mutations within the FVIII
gene have been described in all coding and untranslated
regions. Only one extremely recurrent mutation
has been described: about 40-50 % of severe hemophilia
A cases are caused by a large genomic inversion
of the FVIII gene that separates the first 22 exons from
the final 4 exons. This inversion results from a recombination
between a gene located in intron 22 and either
of two extragenic telomeric homologous genes.
Mutations in the coagulation factor IX (FIX) gene
result in the X-linked recessive bleeding disorder
Hemophilia B, which affects approximately 1 in
30,000 males and very rarely females. The human
FIX gene, located at Xq26-q27, consists of eight
exons that define seven functional domains and
spans approximately 34 kb in the genome transcribed
into an mRNA of 1.4 kb (fig. 2). Hemophilia B is
characterized by a great mutational heterogeneity
with more than 650 different mutations described
along the gene. Since none of these mutations are
clearly predominant in terms of frequency, a suitable
procedure for the molecular diagnosis of the disease
must include a study of all gene essential regions.