The factor IX gene is located at Xq27.1-q27.2 and the gene was fully cloned and sequenced in 1985. The gene is approximately 35 kb in length and consists of eight exons (a-h), producing a 2.8-kb mRNA encoding a mature protein of 415 amino acids (Fig. 2). The putative promoter region is under the control of a number of regulatory elements. Exon a codes for most of the signal peptide, exon b for the propeptide and most of the Gla domain, and exon c codes the remainder of the Gla domain. Exons d and e code for the two EGF-like domains. Exon f codes for the activation peptide, and exons g and h code for the catalytic domain. The stop codon is followed by a 3' untranslated region of 1.4 kb with a polyadenylation recognition sequence.
Many different mutations have been associated with hemophilia B and these are found throughout the factor IX gene. They are mainly point mutations, and no common recurrent mutations have been identified. Missense mutations account for approximately 80% of cases of severe hemophilia B; the remaining 20% of cases are due to gross gene deletions, frameshifts, splice junction changes, and nonsense mutations. Almost all cases of nonsevere hemophilia B are caused by missense muta-tions.
An international factor IX mutation database is available. Over 800 different mutations are reported in the database in association with hemophilia B. In addition to information on point mutations and short additions and deletions, the database also lists tables of gross gene defects and known polymorphisms.
One-third of point mutations occur at CpG dinucleo-tides, and involve a CG ! TG or CA change. The recurrence of some of these mutations in different families supports their role as ''mutation hot spots.'' However, founder effects have also been shown to be responsible for a number of reoccurring mutations in this disorder.
The distribution of mutations between regions of the gene reflects their relative functional importance. Up to half of reported point mutations are in exon h, which codes for the catalytic domain. Similarly, many mutations are found in exon d, which codes for the calcium-binding EGF domain. Hemophilia B has also been associated with changes to 9 of the 12 gamma-carboxyglutamyl residues within the Gla domain, confirming their critical functional role. In addition, substitutions at each of the 22 cysteine residues in factor IX confirm the structural importance of their disulfide linkages.
The risk of development of inhibitors in response to factor IX replacement therapy is determined by the causative mutation and by variations in the immune system of individual patients.
protein domains amino acid no.
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