Golden Blood: Rh Null

What is Rh null?

One of the rarest blood types on Earth. Sorry AB-negative; you’re not the only rare blood type in the world. First discovered in an Aboriginal Australian woman in 1961, the Rh_null (Rhesus null) is one of the rarest and most precious blood types in the world.

… and why is it called “Golden Blood”?

The rarest blood type in existence is Rhnull blood. This stuff is characterized by a complete lack of antigens in the Rh system, which is the largest blood group system. This includes the D antigen (Rh factor, baby), plus the other 50-something antigens in the group.

Who is “The Man with the Golden Arm” James Harrison?

Due to his age, James Harrison was forced to finally retire from donating blood plasma.

Rhnull phenotype is a rare blood group characterized by the lack of expression of all Rh antigens (D, C, c, E and e) on the red cells. The phenotype is further classified into the regulator and amorph type based on underlying genetic defect. The clinical significance of its recognition is that such patients suffer from Rhnull syndrome associated with osmotically fragile red cells called stomatocytes with subsequent chronic haemolytic anaemia of varying degree. Another importance is that such subjects readily form alloantibodies on exposure to Rh antigens.

What is Rh null?

Rhesus (Rh) antigens are defined by a complex association of membrane polypeptides that are missing or severely deficient from the red cells of rare Rhnull individuals who suffer a clinical syndrome of varying severity characterized by abnormalities of the red cell shape, cation transport and membrane phospholipid organization. The Rhnull phenotype is an inherited condition that may arise from homozygosity either for a ‘suppressor’ gene unrelated to the RH locus (‘regulator type’) or for a silent allele at the RH locus itself (‘amorph type’). A current model suggests that the proteins of the Rh complex (Rh, RhAG, CD47, LW, GPB) are assembled by non-covalent bonds and that it is not assembled or transported to the cell surface when one subunit is missing. Rh and RhAG proteins belong to the same protein family and are quantitatively the major components that form the core of the complex, which is firmly linked to the membrane skeleton. Molecular analysis of Rhnull individuals has revealed that abnormalities occur only at the RHAG and RH loci, without alteration of the genes encoding the accessory chains. Mutations of the RHAG gene, but not of RH, occur in all Rhnull individuals of the regulator type (including Rhmod) investigated so far (13 cases), strongly suggesting that RHAG mutants act as ‘suppressors’ and not as transcriptional regulators of the RH genes and that variable expression of the RHAG alleles may account for the Rhmod phenotypes (exhibiting weak expression of Rh antigens). Conversely, mutations of the RHCE gene, but not of RHAG, occur in two unrelated Rhnull individuals of the amorph type, supporting the view that RH mutants result from a ‘silent’ allele at the RH locus. These findings strongly support the Rh complex model since when either the Rh or RhAG protein is missing, the assembly and/or transport of the Rh complex is defective. Transcriptional as well as post-transcriptional mechanisms may account for the molecular abnormalities, but experimental evidence based on expression models is required to test these hypotheses, in the hope that they may help to clarify the biological role of the Rh proteins in the red cell membrane.

How rare/frequent is Rh null really?

Rhnull phenotype is a rare blood group with a frequency of approximately 1 in 6 million individuals, transmitted via an autosomal recessive mode. It is characterized by the weak (Rhmod) or lack (Rhnull) of expression of all Rh antigens on the red cells. The clinical significance of its assessment is that such patients with Rhnull syndrome are associated with chronic hemolytic anemia of varying degrees. Another clinical importance is that such subjects readily form alloantibodies when exposed to Rh antigens.We report herein a rare Rhnull phenotype in a sibling, which was detected as a part of the difficult sample work-up for red cell antibody screening and identification.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305262/

The Rh antigens are thought to play a role in maintaining the integrity of the RBC membrane—RBCs which lack Rh antigens have an abnormal shape.

Individuals with the rare Rh_null phenotype caused by the deletion of RHAG have RBCs that do not express any of the Rh antigens because they cannot be targeted to the RBC membrane. The absence of the Rh complex alters the RBC shape, increases its osmotic fragility, and shortens its lifespan, resulting in a hemolytic anemia that is usually mild in nature. These patients are at risk of adverse transfusion reactions because they may produce antibodies against several of the Rh antigens.

Rh antigens may also be involved in the transport of ammonium across the RBC membrane. Interestingly, the first member of a family of water channels (aquaporins) and the first member of a family of urea transporters were both found in blood group proteins (the Colton blood group and Kidd blood group, respectively).

The genetics of the Rhesus blood group system

To summarize:

Only one antigen, the D antigen determines whether or not you are considered Rh negative, but in reality there are 50 known antigens within the Rh blood group system. If you test negative for the presence of all of them, you are Rh null. If you test negative for the presence of D, even when other antigens from the Rh blood group system are present, you are considered Rh negative.