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Molecular epidemiology of factor IX germline mutations in Mexican Hispanics: pattern of mutation and potential
E C Thorland1, B G Weinshenker, J Z Liu
1Department of Biochemistry and Molecular Biology, Mayo Clinic/Foundation, Rochester, Minnesota 55905, USA.
Abstract:
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.
Insights
Germline mutations causing hemophilia B in Mexican Hispanic and U.S. Caucasian populations show similar patterns, suggesting endogenous processes or a common mutagen. Specific founder mutations offer rapid diagnostic potential.
Area of Science:
- Genetics
- Molecular Biology
- Population Genetics
Background:
- Germline mutations in hemophilia B are recent, often endogenous.
- Exogenous mutagens create distinct mutation patterns.
- Understanding mutation origins is crucial for genetic disease research.
Purpose of the Study:
- To investigate the mutation pattern in the factor IX gene among Mexican Hispanic families with hemophilia B.
- To compare this pattern with U.S. Caucasian families to identify shared or distinct mutational processes.
- To assess the potential of specific recurrent mutations for carrier diagnosis.
Main Methods:
- Dideoxy fingerprinting (ddF) screening of the factor IX gene in 31 Mexican Hispanic hemophilia B families.
- Haplotype analysis to differentiate independent mutations from founder effects.
- Comparative analysis with previously reported mutations in Mexican Hispanic and U.S. Caucasian populations.
Main Results:
- Mutations were identified in 30 of 31 Mexican Hispanic families.
- The mutation pattern in Mexican Hispanics is statistically similar to that in U.S. Caucasians.
- Two recurrent mutations (T296M and R248Q) account for 19% of mutations in Mexican families and are linked to founder effects.
- Identical founder mutations in both populations suggest a limited number of mutations cause mild hemophilia B.
Conclusions:
- The observed mutation patterns suggest either endogenous processes or an ubiquitous mutagen.
- Specific founder mutations (T296M, R248Q) in the factor IX gene are valuable for rapid mutation detection and carrier diagnosis in Mexican Hispanic populations.
- Independent origins of identical founder mutations in different populations support the hypothesis of a limited mutational spectrum for mild hemophilia B.