Molecular Basis of the Kell-null Phenotype: A MUTATION AT THE SPLICE SITE OF HUMAN KEL GENE ABOLISHES THE EXPRESSION OF KELL BLOOD GROUP ANTIGENS

Abstract

The Kell blood group system is polymorphic, and 23 antigens have been defined to date. The Kell antigens are located on a single red cell transmembrane glycoprotein, encoded by the 19 exons of the KEL gene. The different Kell phenotypes result from point mutations leading to amino acid changes in the Kell glycoprotein. An unusual phenotype, which is defined as the complete lack of all of the Kell antigens, has been identified and designated as the Kell-null or Ko phenotype. The coding region of the KEL gene of the Ko individual showed a normal KEL2/KEL4/KEL7 gene sequence; nevertheless, a G to C mutation at the splice donor site (5' splice site) of intron 3 was found to be present as a homozygote in the individual. The mutation destroys the conserved GT sequence of the splice donor site. Reverse transcription-polymerase chain reaction analysis showed the absence of the complete KEL mRNA. Instead, a major transcript with the exon 3 region skipped was found. The exon 3 of the KEL gene encodes the transmembrane domain of the Kell glycoprotein, and a transcript without exon 3 is predicted to have a premature stop codon that abolishes the translation of C-terminal segment. The segment contains all of the known positions responsible for characterizing different Kell antigens, and this explains the lack of all Kell antigens in Ko red cells.