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J. Biol. Chem., Vol. 277, Issue 33, 29455-29459, August 16, 2002

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Molecular Basis of the Globoside-deficient P^k Blood Group Phenotype
IDENTIFICATION OF FOUR INACTIVATING MUTATIONS IN THE UDP-N-ACETYLGALACTOSAMINE: GLOBOTRIAOSYLCERAMIDE 3--N-ACETYLGALACTOSAMINYLTRANSFERASE GENE^*

Åsa Hellberg, Joyce Poole^§, and Martin L. Olsson^¶

From the  Department of Transfusion Medicine, Institute of Laboratory Medicine, Lund University and Blood Centre, University Hospital, SE-22185 Lund, Sweden and the ^§ International Blood Group Reference Laboratory, BS105ND Bristol, United Kingdom

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 P₁^k and P₂^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 (C²⁰²  T and 538insA) resulting in premature stop codons was found in blood samples from two individuals of the P₂^k phenotype. Two individuals with P₁^k and P₂^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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF494103, AF494104, AF494105, AF494106.

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