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Aberrant intracellular trafficking of a variant B glycosyltransferase
Author(s) -
Seltsam Axel,
Grüger Daniela,
Just Burkhard,
Figueiredo Constança,
Gupta Christa Das,
DeLuca David S.,
Blasczyk Rainer
Publication year - 2008
Publication title -
transfusion
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.045
H-Index - 132
eISSN - 1537-2995
pISSN - 0041-1132
DOI - 10.1111/j.1537-2995.2008.01782.x
Subject(s) - abo blood group system , glycosyltransferase , allele , exon , biology , mutation , haplotype , phenotype , microbiology and biotechnology , gene , genetics
BACKGROUND: Little is known about the mechanism by which amino acid polymorphisms outside the catalytically active cleft of ABO glycosyltransferases cause weak ABO phenotypes. STUDY DESIGN AND METHODS: Extensive ABO phenotyping and genotyping were performed to classify the blood of a healthy blood group O donor with weak isoagglutinins. ABO antigen and glycosyltransferase expression profiles were then studied in eukaryotic transfection experiments, and the topology of ABO glycosyltransferase was analyzed. RESULTS: The donor's red blood cells were retyped as A weak , and his serum contained weakly reactive anti‐A and anti‐B. Sequence analysis revealed two novel ABO alleles. A donor splice‐site mutation detected at the exon 6/intron 6 junction of an ABO * A101 allele was predicted to result in skipping exon 6 in the mRNA. The other haplotype displayed a single 688G>C substitution predicting a Gly230Arg exchange in the catalytic domain in an otherwise normal ABO * B101 allele. The transfection studies revealed very weak expression of B antigen by the novel ABO * B allele. According to the topologic analysis, steric hindrance due to the Gly230Arg exchange may cause conformational changes in the variant B transferase. Compared to the wild‐type B transferase, the transfected cells exhibited lower‐level protein expression and intracellular dislocation. CONCLUSION: This study provides first evidence that aberrant trafficking of variant ABO transferases may be involved in the formation of weak ABO phenotypes.