Molecular Basis of the Globoside-deficient Pk Blood Group Phenotype

Abstract

The biochemistry and molecular genetics underlying the related carbohydrate blood group antigens P, P k , and LKE in the GLOB collection and P1 in the P blood group system are complex and not fully understood. Individuals with the rare but clinically important erythrocyte phenotypes P 1 k and P 2 k lack the capability to synthesize P antigen identified as globoside, the cellular receptor for Parvo-B19 virus and some P-fimbriated Escherichia coli. As in the ABO system, naturally occurring antibodies, anti-P of the IgM and IgG class with hemolytic and cytotoxic capacity, are formed. To define the molecular basis of the P k phenotype we analyzed the full coding region of a candidate gene reported in 1998 as a member of the 3-␤-galactosyltransferase family but later shown to possess UDP-N-acetylgalactosamine:globotriaosylceramide 3-␤-N-acetylgalactosaminyltransferase or globoside synthase activity. Homozygosity for different nonsense mutations (C 202 3 T and 538insA) resulting in premature stop codons was found in blood samples from two individuals of the P 2 k phenotype. Two individuals with P 1 k and P 2 k phenotypes were homozygous for missense mutations causing amino acid substitutions (E266A or G271R) in a highly conserved region of the enzymatically active carboxyl-terminal domain in the transferase. We conclude that crucial mutations in the globoside synthase gene cause the P k phenotype.

Drosophila egghead Encodes a β1,4-Mannosyltransferase Predicted to Form the Immediate Precursor Glycosphingolipid Substrate for brainiac

“…Mice deficient in ganglioseries glycolipids built on GalNAc␤1-4Gal␤1-4Glc␤1-Cer have yielded significant information (17)(18)(19)(20)(21). Globoseries glycolipids built on Gal␣1-4Gal␤1-4Glc␤1-Cer are dispensable in man as evidenced from the rare P k and p blood groups (22,23). While the biosynthesis of ganglioseries and globoseries glycolipids are carried out by unique single copy genes, each step in the biosynthesis of lacto-and neolactoseries glycolipids based on the fact that GlcNAc␤1-3Gal␤1-4Glc␤1-Cer is carried out by multiple isoenzymes, many of which serve functions in the synthesis of glycoproteins as well (24).…”

Human Genetic Determinants of Viral Diseases

“…Likewise, cells from P-negative donors could not be infected, even at extreme doses (15). To date, P-negative phenotypes have been attributed to several rare polymorphisms in two genes, B3GALNT1 and A4GALT, which encode glycosyltransferases involved in distinct steps of P antigen biosynthesis (48, 138, 165, 166). …”

Molecular genetic basis of the human Forssman glycolipid antigen negativity

“…For instance, non-functional alleles are known to exist for the B3GALNT1 gene encoding β1,3- N -acetyl-D-galactosaminyltransferase 1, which catalyzes the biosynthesis of globoside, the acceptor substrate of FS. Those individuals who are homozygous of the non-functional alleles cannot produce globoside and exhibit the P k phenotype of the P blood group system2627. Therefore, the inactivating mutations of the B3GALNT1 gene can also be regarded as a cause of Forssman glycolipid antigen negativity.…”