GOLDEN GATE DIETETIC INTERNSHIP
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Dean L. Blood Groups and Red Cell Antigens
The antigens of the Diego blood group are carried on an important protein, called theband 3 protein, which lies in the red blood cell (RBC) membrane. This protein is achloride/bicarbonate exchanger involved in carbon dioxide transport from tissues tolungs. It also is found in the kidney, where it is involved in acid secretion.
Many mutations in the gene that encodes the Diego antigens, SLC4A1, are known. Thesemutations can result in RBCs with an abnormal membrane (hereditary ovalocytosis andspherocytosis) and kidneys that are defective in secreting acid (renal tubuleacidosis). Other SLC4A1 mutations that do not give rise to disease may result in newblood group antigens that belong to the Diego blood group system.
| Number of antigens | 21: Dia, Dib, and Wra areamong the most significant |
| Antigen specificity | ProteinAmino acid sequence determines thespecificity of Diego antigens |
| Antigen-carrying molecules | Glycoprotein that transports anionsThe Diegoprotein is a transmembrane, multi-pass protein that is integral tothe RBC membrane. It is an anion antiporter that exchangesCl- and HCO3- across the RBC membrane. |
| Molecular basis | The SLC4A1 gene encodes the Diegoantigens.Located on chromosome 17 (17q21-22), theSLC4A1 gene contains 20 exons that span more than 18 kbp of DNA. Thealleles Dib and Dia result from a SNP(2561C→T), and the corresponding Dib andDia antigens differ by a single amino acid(P854L). |
| Frequency of Diego antigens | Dia is found mainly inpopulations of Mongolian descent. It is found in36% of South American Indians, 12% of Japanese, and 12% of Chinese,whereas it is rare in Caucasians and Blacks (0.01%).Dib is found universally in mostpopulations (1). |
| Frequency of Diego phenotypes | Di(a-b+) is found in >99.9%of Caucasians and Blacks and >90% ofAsians.Di(a+b+) found in <0.1% of Caucasiansand Blacks and in 10% Asians.Di(a+b-) found in <0.01%Caucasians, Blacks, and Asians.Di(a-b-) found in 1 case only(1). |
| Antibody type | IgG or IgMAnti-Dia andanti-Dib is IgG; anti-Wra is IgG or IgM (1). |
| Transfusion reaction | YesAnti-Dia and anti-Dibare capable of causing a moderate to severe delayed transfusionreaction. Anti-Wra can cause an immediate hemolytictransfusion reaction (1). |
| Hemolytic disease of the newborn | Yes Anti-Dia and anti-Wracan cause severe disease. Anti-Dib tends to causemild hemolytic disease (1). |
History
The Diego blood group was discovered in 1955 and was named for the first patientto produce an antibody against the new blood system"s antigens. The patient,Mrs. Diego, had given birth to a child affected by HDN. Her serum was found tocontain an antibody (now called anti-Dia) which, during herpregnancy, had crossed the placenta to attack the RBCs of her fetus (whichexpressed the Dia antigen).
In 1967, a second Diego antigen, Dib, was discovered. It wasn"t until1995 that other Diego antigens began to be discovered.
At present, 21 Diego antigens are known, but it is the presence or absence ofDia and Dib that is of importance in determining aperson"s Diego blood type.
Note: The alternate gene symbol is AE1, which stands for Anion Exchanger 1. Thealternate gene name is erythrocyte membrane protein band 3.
Common phenotypes
The most common Diego phenotype is Di(a-b+), which is found in over 99.9%Caucasians and Blacks, and over 90% of Asians. The Di(a+b+) is found in 10% ofAsians. Whereas the Dia antigen is universally expressed in mostpopulations, the prevalence of the Dia antigen differs among races,making the Diego blood group of great interest to anthropologists (3).
In the USA, the Dia antigen has not been found in Caucasian or Blackblood donors (4). TheDia antigen is more commonly found in Oriental people of Mongoliandescent, being more common in the Japanese (12%) and the Chinese (5%). In SouthAmerican Indians, up to 54% of the population carries the Dia antigen(1).
Interestingly, the Dia antigen is less rare in the Polish population(0.47%) (5) compared to mostCaucasian populations (0.01%). This may reflect the gene admixture that resultedfrom the invasion of Poland by Tatars (Mongolian heritage) many centuries ago(6).
Expression of Diego antigens
The expression of Diego antigens is limited to RBCs and the kidney (in the distaltubule and the collecting tubule).
Anion exchange across the RBC membrane
The SLCA41 protein is an anti-porter that plays an essential role in enablingthe RBC to transport the waste product CO2 to the lungs, where itcan be removed from the body.
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The SLCA41 protein exchanges one Cl- for one HCO3-. Thedirection of the exchange depends on the concentration of the ions on eitherside of the RBC membrane. When levels of waste CO2 are high,CO2 diffuses across the RBC membrane and is converted intoHCO3- which is transported out of the RBC in exchange forCl-. If anion exchange did not occur, HCO3- wouldaccumulate inside the RBC and reach toxic levels, altering the intracellularpH. In the lungs, the lower level of CO2 encourages the directionof the exchange to reverse. Once inside the RBC, the HCO3- yieldsCO2 which diffuses out of the RBC and is exhaled from thebody.
Integral protein of the RBC membrane
The SLCA1 protein is an integral part of the RBC membrane. It helps anchorthe membrane to the underlying spectrin skeleton. It helps the RBC to bestable and flexible, and maintain its biconcave shape.
Mutations of SLC4A1 can cause abnormally shaped RBCs that may be spherical(spherocytes, seen in hereditary spherocytosis), oval shaped (ovalocytes,seen in Southeast Asian ovalocytosis), or elliptical (elliptocytes). Becausethese RBCs are more fragile, they are prematurely removed from thecirculation (hemolytic anemia).
Anion exchange across in the kidney tubule
SCLA1 is expressed in the kidney, where it also mediates the exchange ofanions. Mutations that disrupt its function can cause a renal tubularacidosis in which the kidney fails to adequately excrete acid anions,allowing them to accumulate.
Transfusion reactions
Anti-Dia and anti-Dib are more commonly associated with HDNthan transfusion reactions. However, these antibodies are capable of causingimmediate (9) and delayedhemolytic transfusion reactions (2,8).
Hemolytic disease of the newborn
HDN caused by Diego antibodies are more common in South East Asia and SouthAmerica.
Anti-Dia is capable of causing moderate to severe HDN, and cases havebeen reported in Japan (9),China (10, 11), and Poland(5).
Anti-Dib typically causes mild HDN. Cases have been reported in Japan(12), China (13), Poland (6), and in a mother of SouthAmerican descent (14).
Gene
The SLC4A1 gene, also known as the AE1 gene, is a member of the anionexchanger (AE) gene family. SLC4A1 is located on chromosome 17q21-q22 andconsists of 20 exons that are distributed over almost 18 kbp of genomic DNA.
The Dia and Dib antigens are produced as a result of asingle nucleotide polymorphism (SNP) of the SLC4A1 gene. The result is at aminoacid position 854; the common (wild-type) Dib antigen has a prolineresidue, and the Dia antigen has a leucine residue.
Protein
The band 3 protein encoded by SLC4A1 is an important integral protein of the RBCmembrane. It is 911 amino acids in length, and it loops across the RBC membrane12 times.
The N terminal domain of the protein lies in the cytoplasm of the RBC, where itinteracts with hemoglobin (influencing the exchange of anions) and alsointeracts with metabolic enzymes (influencing the metabolism of glucose insidethe RBC).
Its C-terminal domain spans across the membrane of the RBC and mediates theexchange of chloride and bicarbonate anions across the membrane.
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