Molecular genetics of human carbohydrate defined blood groups. Studies of the ABO and P blood group systems

Abstract: The aim of this study was to explore the molecular genetics of the carbohydrate defined blood group ABO and P systems.The blood group ABO system is the clinically most significant system in transfusion medicine. Using modern molecular biology, a number of the ABO alleles have been characterized. The phenotypes associated with these alleles have been shown to be a consequence of point mutations or deletions leading to (presumed) inactive or partly inactive glycosyltransferases. At the onset of this project, analysis of the ABO genes was hindered by lack of knowledge of the genomic organisation. The first part of this study therefore deals with the genomic organisation of the coding region, which was found to span seven exons. During our studies a new blood group O allele, designated O2 was identified. This new allele has a different inactivation mechanism than previously identified O alleles.The second part of this study aimed at gaining insight into the molecular genetics of the P blood group system, which is the last of the carbohydrate defined blood group systems to be elucidated. Using modern bioinfomatics and data from the human genome resources a gene, homologous to a new a4GlcNAc-transferase located on chromosome 3p14.3, was identified, cloned and expressed. The novel gene encoded an enzyme with Pk activity and a single homozygous missense mutation M183K was found in six Swedish individuals with the rare p phenotype. The mutant gene was inactive confirming that this gene represented Pk synthase. Although the gene appears to colocalize on chromosome 22 with the previously P1 polymorphism, the expressed enzyme did not function as a P1 synthase. The implications for the P1 genotype are discussed.