The RHD gene is flanked by two DNA segments of 9000 bp, called Rhesus boxes. The RHD deletion occurred by a recombination of the upstream and downstream Rhesus boxes and led to a RH locus, which closely resembles the ancestral state before the RH duplication occurred. At the insertion point, a 9000-bp DNA segment is duplicated, resulting in the formation of upstream and downstream Rhesus boxes, which flank the RHD gene. In the duplication event, an inversed RH gene is introduced between NPD014 and SMP1. Two other genes, the P29-associated protein (P) and NPD014 (N) are upstream of SMP1. In the ancestral state (deduced from the mouse RH locus), a single RH gene is in close proximity to the SMP1 gene. Furthermore, the distorted RBC shape in the Rh null phenotype indicates the importance of the correct interaction of the Rh complex with the cytoskeleton. 13– 15 Currently, it is unknown whether this represents their sole function indirect data 16 feed speculation on transport functions for other gases more relevant to the RBCs, such as CO 2 or O 2. The RhAG and Rh proteins share homologies with ammonia transport proteins and have been shown to transport ammonia. The membrane expression of Rh depends on functional RhAG: mutations in RhAG could be shown to underly the “regulator form” of the Rh null phenotype characterized by lack of all Rh antigens. 11 Several additional proteins, such as CD47, LW, and the Duffy glycoprotein, are associated with the Rh complex but not necessary for Rh expression. 10 This “Rh complex” is tightly linked to the cytoskeleton. In the RBC membrane, the Rh proteins form a complex with Rh-associated glycoprotein (RhAG), previously known as RH50. The latter fact is most important for D antigen expression and is discussed in detail in the text. Most differences are located in transmembranous or intracellular segments among the extracellular loops, only loops 3, 4, and 6 differ between RhD and RhCE. Each amino acid is depicted by a circle black circles indicate positions that differ between RhD and RhCE in all frequent alleles, grey circles indicate positions that differ between RhD and RhCE only in some alleles.

Both the C- and N-terminal ends of the protein are intracellular. The protein is assumed to possess 12 transmembranous segments, 6 extracellular loops, and 5 intracellular loops.

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