Researchers looking into a 50-year-old mystery surrounding a rare missing antigen have discovered a new blood group system called MAL. 

Your blood type is determined by the presence or absence of specific antigens, with the main types people know being A, B, O, and AB (positives and negatives). However, blood groups are slightly different. 

"The term 'blood group' refers to the entire blood group system," a 2014 paper on the topic explains, "comprising red blood cell antigens whose specificity is controlled by a series of genes."

There are this many groups because there are many ways of grouping red blood cells based on the antigens on their surfaces. As of November 2023, there were 45 recognized distinct blood group systems, according to the International Society of Blood Transfusion, containing 362 red cell antigens.

Following an investigation into a mystery 50 years old, we may have to add another group to the already quite long list. 

In 1972, a pregnant woman's blood was tested, and she was found to not have a highly prevalent red blood cell antigen. The antigen, which they dubbed AnWj after two patients who lack it, is missing in only a handful of people that scientists know of. The most common reason for missing it are cancers that suppress antigen expression, and hematological disorders. However, five individuals identified in the new study, including several members of one family, appear to lack it due to a genetic cause. 

"The AnWj-negative phenotype is usually caused by transient suppression of antigen expression, associated with certain haematological disorders and malignancies," the team explains in their study. "Such suppression of blood group antigens, with associated antibody production against the suppressed antigen, is an established phenomenon, seen for example in Kell, Kidd and LW systems. In such cases, it has been hypothesised that acquired reduction of antigen expression on the patient’s red cells leads to development of the antibody, typically during pregnancy or following transfusion."

Analyzing the patients' exomes – which is the genetic sequencing that encodes proteins – the team found specific homozygous DNA sequence deletions in the gene that codes for the myelin and lymphocyte protein, known as the MAL gene.

"AnWj-positive individuals were shown to express full-length Mal on their red cell membranes, which was not present on the membranes of AnWj-negative individuals, whether of an inherited or suppression background," the team continued. "Furthermore, binding of anti-AnWj was able to inhibit binding of anti-Mal to AnWj-positive red cells, demonstrating the antibodies bind to the same molecule."

The team named the new blood group system, defined by whether you have this antigen or not, as MAL. 

“The genetic background of AnWj has been a mystery for more than 50 years, and one which I personally have been trying to resolve for almost 20 years of my career. It represents a huge achievement, and the culmination of a long team effort, to finally establish this new blood group system and be able to offer the best care to rare, but important, patients," Louise Tilley, Senior Research Scientist, IBGRL Red Cell Reference at NHS Blood and Transplant, said in a statement. 

“The work was difficult because the genetic cases are very rare. We would not have achieved this without exome sequencing, as the gene we identified wasn’t an obvious candidate and little is known about Mal protein in red cells. Proving our findings was challenging, and we appreciate the help of all our collaborators, and the patients, without whom we would not have got to this point.”

The presence of alloantibodies can cause problems during transfusion if there is a mismatch between donor and recipient, as well as triggering attacks on the immune system during pregnancy. Though lacking this specific antigen is incredibly rare, knowing about it will help keep patients safe during blood transfusions, reducing the chance of such adverse transfusion reactions. 

The study is published in Blood, the journal of the American Society of Hematology.