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Haemophilia A and haemophilia B: molecular insights

Correspondence to:
D J Bowen, Department of Haematology, University of Wales College of Medicine, Heath Park, Cardiff CF3 0DQ, South Wales, UK;
bowendj1{at}cf.ac.uk

ABSTRACT
This review focuses on selected areas that should interest both the scientist and the clinician alike: polymorphisms within the factor VIII and factor IX genes, their linkage, and their ethnic variation; a general assessment of mutations within both genes and a detailed inspection of the molecular pathology of certain mutations to illustrate the diverse cause–effect relations that exist; a summary of current knowledge on molecular aspects of inhibitor production; and an introduction to the new areas of factor VIII and factor IX catabolism. An appendix defining various terms encountered in the molecular genetics of the haemophilias is included, together with an appendix providing accession numbers and locus identification links for accessing gene and sequence information in the international nucleic acid databases.

View larger version (14K): [in this window] [in a new window]   Figure 4 (A) Genomic organisation of the human factor IX gene. Exon and intron sizes are given in table 2. (B) Factor IX mRNA showing the relative size and location of the open reading frame. (C) The newly synthesised factor IX protein molecule comprising a pre- and pro-sequence (27 and 19 amino acids, respectively) and a mature peptide of 415 amino acids (total length, 461 amino acids). (D) Activated factor IX comprising an N-terminal light chain and a C-terminal heavy chain held together by a disulphide bridge between cysteine resides 132 and 279. GLA, "GLA" domain, in which 12 glutamic acid residues undergo post-translational -carboxylation by a vitamin K dependent carboxylase; EGF, epidermal growth factor-like domain; act, activation peptide released after proteolytic activation at arginine 145 and arginine 180; catalytic, the serine protease domain.

View larger version (13K): [in this window] [in a new window]   Figure 11 Mutations as a result of CG transitions at the codons encoding the activation cleavage site arginine residues of (A) factor VIII and (B) factor IX.

Keywords: haemophilia A; haemophilia B; factor VIII; factor IX; polymorphism; mutation; inhibitor; catabolism

Abbreviations: ARE, androgen response element; C/EBP, CCAAT/enhancer binding protein; EGF, epidermal growth factor; LD, long distance; LRP, lipoprotein receptor related protein; MHC, major histocompatibility complex; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism; SNP, single nucleotide polymorphism; VNTR, variable number tandem repeat sequence

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