WIDE VARIETY OF POINT MUTATIONS IN THE H-GENE OF BOMBAY AND PARA-BOMBAY INDIVIDUALS THAT INACTIVATE H-ENZYME

The H genes, encoding an alpha 1,2 fucosyltransferase, which defines b lood groups with the H structure, of four Bombay and 13 para-Bombay Ja panese individuals were analyzed for mutations. Four Bombay individual s were homologous for the same null H allele, which is inactivated by a single nonsense mutation at position 695 from G to A (G695A), result ing in termination of H gene translation. The allele inactivated by th e G695A was designated h1. The other 13 para-Bombay individuals posses sed a trace amount of H antigens on erythrocytes regardless of their s ecretor status. Sequence analysis of their H genes showed four additio nal inactivated H gene alleles, h2, h3, h4, and h5. The h2 allele poss essed a single base deletion at position 990 G (990-del). The h3 and h 4 alleles possessed a single missense mutation, T721C, which changes T yr 241 to His, and G442T, which changes Asp148 to Tyr, respectively. T he h5 allele possessed two missense mutations, T460C (Tyr154 to His) a nd G1042A (Glu348 to Lys). The h2, h3, h4, and h5 enzymes directed by these alleles were not fully inactivated by the deletion and the misse nse mutations expressing some residual enzyme activity resulting in sy nthesis of H antigen on erythrocytes. Thirteen para-Bombay individuals whose erythrocytes retained a trace amount of H antigen were determin ed to be heterozygous or homozygous for at least one of h2, h3, h4, or h5 alleles. This clarified that the levels (null to trace amount) of H antigen expression on erythrocytes of Bombay and para-Bombay individ uals are determined solely by H enzyme activity. These mutations found in the Japanese H alleles differ from a nonsense mutation found in th e Indonesian population. To determine the roles of the H, Se, and Le g enes in the expression of H antigen in secretions and Lewis blood grou p antigen on erythrocytes, the Lewis and secretor genes were also exam ined in these Bombay and para-Bombay individuals. The Lewis blood grou p phenotype, Le(alpha(-) b(+)), was determined by the combinatorial ac tivity of two fucosyltransferases, the Lewis enzyme and the secretor e nzyme, and the secretor status was solely determined by the secretor e nzyme activity, not by H enzyme activity. Bombay individuals were conf irmed to be homozygous for the inactivated H and Se genes. As expected from the Very low frequency of Bombay and para-Bombay individuals in the population, ie, approximately one in two or 300,000, the H gene mu tations were found to be very variable, unlike the cases of the point mutations in the other glycosyltransferase genes; the ABO genes, the L ewis gene, and the secretor gene. (C) 1997 by The American Society of Hematology.