The structure and function of the Rh antigen complex

Abstract

The Rh system is one of the most important and complex blood group systems because of the large number of antigens and the serious complications for the fetus of a woman sensitized by transfusion or pregnancy. Major advances in our understanding of the Rh system have occurred with the cloning of the genes and with functional evidence that the Rh blood group proteins belong to an ancient family of membrane proteins involved in ammonia transport. The arrangement and configuration of the genes at the RH locus promotes genetic exchange, generating new antigens. Importantly, RH genetic testing can now be applied to clinical transfusion medicine and prenatal practice. This includes testing for RHD zygosity, confirmation or resolution of D antigen status, and detection of altered RHD and RHCE genes in individuals at risk for producing antibodies to high-incidence Rh antigens, particularly sickle cell disease (SCD) patients. The Rh proteins form a core complex that is critical to the structure of the erythrocyte membrane, and they may play a physiologic role in the sequestration of blood ammonia. The Rh family of proteins now includes non-erythroid homologs present in many other tissues, and comparative genomics reveal Rh homologs in all domains of life.

Fig. 1

A). Diagram of the RHD and RHCE locus. The two RH genes have opposite orientation, with the 3′ends facing each other. Rh negative Caucasian individuals have a complete deletion of RHD. B). Rh proteins in the RBC membrane. The RhD and RhCE proteins are predicted to have twelve transmembrane domains. Amino acid positions that differ between RhD and RhCE are shown as dark circles on RhD. The amino acid changes responsible for C/c and E/e polymorphisms are shown on RhCE.

Fig. 2

Diagram of amino acid changes in RhD proteins shown as circles. A). Weak D phenotypes. Amino acid changes that cause weak D expression, shown as circles, are located predominantly in transmembrane and cytoplasmic regions. Weak D Type 1 (V270G) predominates in Europeans, as well as Type 2 and Type 3, which together represent the majority of weak D, are indicated. B). Partial D phenotypes. Amino acid changes that cause some partial D phenotyes are predicted to be located in the extracellular loops. The DNB mutation is frequent in Europeans. C). Del phenotypes. Amino acid changes that severely reduce the quantity of RhD resulting in RBCs that type serologically D-negative are shown. The scribble line indicates loss of the 3′ region, characteristic of Asian mutations, and the European M295I mutation is shown in transmembrane nine.

Fig 3

Most Parital D phenotypes result from gene conversion. The ten RHD exons are shown as white boxes, and the RHCE as grey. Some examples of new antigens that result from hybrid proteins encoded by regions of RHCE inserted in RHD are indicated. For a comprehensive summary, see the Facts Book.

Fig. 4

Diagram of the RHD and RHCE genes. The ten RHD exons are shown as white boxes, and the RHCE as grey. A). RHD and RHCE genes responsible for the common D, C, c, E and e antigen polymorphisms. B). Altered RHD and C). Altered RHCE genes indicating the changes often found in African-Americans that complicate transfusion, especially for sickle cell patients.