Mazin
A.L.
Methylation of the Factor IX Gene is a Main
Cause of Mutations Responsible for Hemophilia B.
Molec. Biol. 1995, vol.29,
n.1, pp.73-92.
A total of 750 mutations
in the human coagulation factor IX gene in 806 patients with hemophilia
B were analyzed. It was found that 40% of all point mutations occur
in 11 "hot spots," which are CG methylation sites where
*CG-to-TG or *CG-to-CA substitutions take place. A mechanism is proposed
which explains the high frequency of such transitions by m5C
deamination during the replicative DNA methylation and by misrepairing
G:T pairs. Such processes may be one of the main sources of mutations
in this gene, which repeatedly occur de novo and support the incidence
of hemophilia B with a high frequency. Asymmetry of C-to-T and G-to-A
transition mutations was found in a number of CG sites of the complementary
DNA strands. It is a result of "silent" mutations, which
usually escape detection. When such substitutions are taken into account,
it becomes evident that cytosine methylation in the factor IX gene
may generate up to 50% of all point mutations. This is why the rate
of mutations at CG sites is 48-fold higher than at any other dinucleotides
of the gene. As a result of such mutations, at least 35 new CG sites
originate sporadically in the gene. De novo methylation and
mutation of these sites may cause up to 14% of all the observed point
substitutions in the factor IX gene. The origin of the T-to-C "hot
spot" in the Ile397 codon may
be explained not only by the "founder effect" but also by
recessive mutations in such CG site in the maternal ancestors. It
was calculated that methylation of *CNG sites as well as misrepairing
G:T pairs potentially may cause up to 5,4% of mutations. Summing up,
from 50 to 70% of all point mutations in the human factor IX gene
may occur through cytosine methylation. Analysis of doublet frequencies
showed that as a result of "fossil" methylation approximately
60 CG sites could vanished and 8% of *CG-to-TG+CA substitutions accumulated
in the factor IX gene. The remaining 20 CG sites are located in the
codons of the amino acids, which are crucial for this protein activity.
It is concluded that cytosine methylation may be one of the major
causes of point mutations in the factor IX gene responsible for Hemophilia
B.
