Molecular basis of weak D phenotypes

A Rhesus D (RhD) red blood cell phenotype with a weak expression of the D a ntigen occurs in 0.2% to 1% of whites and is called weak D, formerly D-u. R ed blood cells of weak D phenotype have a much reduced number of presumably complete D antigens that were repeatedly reported to carry the amino acid sequence of the regular RhD protein. The molecular cause of weak D was unkn own. To evaluate the molecular cause of weak D, we devised a method to sequ ence all 10 RHD exons, Among weak D samples, we found a total of 16 differe nt molecular weak D types plus two alleles characteristic of partial D. The amino acid substitutions of weak D types were located in intracellular and transmembraneous protein segments and clustered in four regions of the pro tein (amino acid positions 2 to 13, around 149, 179 to 225, and 267 to 397) . Based on sequencing, polymerase chain reaction-restriction fragment lengt h polymorphism and polymerase chain reaction using sequence-specific primin g, none of 161 weak D samples investigated showed a normal RHD exon sequenc e. We concluded, that in contrast to the current published dogma most, if n ot all, weak D phenotypes carry altered RhD proteins, suggesting a causal r elationship. Our results showed means to specifically detect and to classif y weak D, The genotyping of weak D may guide Rhesus negative transfusion po licy for such molecular weak D types that were prone to develop anti-D, (C) 1999 by The American Society of Hematology.