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 patter ns of mutation. In contrast, endogenous mutation processes likely are associated with an invariant pattern of mutation. Analysis of factor I X gene mutations among large samples of hemophilia B patients from mul tiple, widely divergent geographic and ethnic populations reveals a re markably constant mutational pattern, suggesting that the primary germ line mutational process results from endogenous processes rather than environmental mutagens. To test this hypothesis further, we have initi ated a study of hemophilia B patients from Peru because relatively lar ge populations of AmerIndians can be found with low admixtures of othe r races. To determine if the factor LY (FIX) germline mutational patte rn in AmerIndians differs from the common and putative endogenous patt ern, 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 e xons, the splice junctions, and the promoter region. The pattern of ge rmline mutation in AmerIndians vc as similar to the pattern of FIX ger mline mutations from larger U.S. Caucasian or Mexican Hispanic samples (P = 0.55 and 0.63, respectively). The similar pattern in this initia l sample of the Peru AmerIndian population provides additional support for the inference that the FIX germline mutational pattern results fr om predominantly endogenous processes rather than exogenous mutagens. (C) 1998 Wiley Liss, Inc.