Germline mutations in Peruvian patients with hemophilia B: pattern of mutation in AmerIndians is similar to the putative endogenous germline pattern.

Exogenous (e.g., environmental) mutagens produce characteristic patterns of mutation. In contrast, endogenous mutation processes likely are associated with an invariant pattern of mutation. Analysis of factor IX gene mutations among large samples of hemophilia B patients from multiple, widely divergent geographic and ethnic populations reveals a remarkably constant mutational pattern, suggesting that the primary germline mutational process results from endogenous processes rather than environmental mutagens. To test this hypothesis further, we have initiated a study of hemophilia B patients from Peru because relatively large populations of AmerIndians can be found with low admixtures of other races. To determine if the factor IX (FIX) germline mutational pattern in AmerIndians differs from the common and putative endogenous pattern, FIX gene mutations were characterized in an initial sample of 10 AmerIndian Peruvian patients with hemophilia B. A minimum of 2.2 kb of the FIX gene was examined by PCR and direct sequencing of all eight exons, the splice junctions, and the promoter region. The pattern of germline mutation in AmerIndians was similar to the pattern of FIX germline mutations from larger U. S. Caucasian or Mexican Hispanic samples (P=0.55 and 0.63, respectively). The similar pattern in this initial sample of the Peru AmerIndian population provides additional support for the inference that the FIX germline mutational pattern results from predominantly endogenous processes rather than exogenous mutagens.

Molecular epidemiology of factor IX germline mutations in Mexican Hispanics: pattern of mutation and potential founder effects.

Germline mutations in patients with hemophilia B generally have arisen within the past 150 years. Evidence suggests that these germline mutations generally result from endogenous processes. However, a unique pattern would be expected if a population were exposed to a physiologically important germline mutagen since mutagens generally produce characteristic patterns, or "fingerprints", of mutation. To determine the pattern of mutation in Mexican Hispanics, the regions of likely functional significance in the factor IX gene were screened by dideoxy fingerprinting (ddF) in 31 families with hemophilia B. Mutations were found in 30 of these families. Haplotype analysis was performed on individuals with identical mutations to help distinguish independent, recurrent mutations from founder effects. Analysis of these 30 mutations, along with 7 mutations reported previously in Mexican Hispanic families, reveals a pattern of independent mutation that is similar to the pattern of mutation observed in 127 U.S. Caucasian families (p = 0.89). These results may reflect either an underlying pattern of germline mutation due to endogenous processes or the presence of an ubiquitous mutagen. Further analyses of the recurrent mutations revealed that two mutations, T296M and R248Q, accounted for 19% of the mutations found in the Mexicans. Haplotype data suggest that the multiple occurrences of T296M and R248Q are associated with founder effects and that screening for these mutations may allow rapid mutation detection and carrier diagnosis in a significant minority of Mexican families with hemophilia B, These two mutations also are associated with founder effects in the U.S, Caucasian population. However, the haplotypes are different in these two populations, indicating independent origins. The occurrence of identical founder mutations in distinct populations provides evidence for the previous hypothesis that the number of different mutations giving rise to mild or borderline mild/moderate hemophilia B is small compared to deleterious mutations causing more severe disease.