A decades-long search to identify a mysterious blood antigen has led researchers to a hidden genetic difference found in a tiny number of people.
A rare blood type mystery that has puzzled scientists for over 50 years has finally been solved, and the breakthrough could make blood transfusions safer for patients around the world.
Researchers in the United Kingdom and Israel have identified the genetic cause behind the elusive AnWj blood group, leading to the recognition of an entirely new blood group system called MAL. The discovery not only ends a decades-long scientific search, but also opens the door to improved screening for people with extremely rare blood types who may face dangerous transfusion reactions.
The findings were led by NHS Blood and Transplant through its International Blood Group Reference Laboratory (IBGRL) in Bristol, with contributions from the University of Bristol and several international partners. The study was published in Blood, the journal of the American Society of Hematology.
Beyond ABO: The Hidden Complexity of Blood
Most people know their blood type as A, B, AB, or O, along with positive or negative Rh status. But those familiar categories represent only a small part of human blood diversity.
Scientists have now identified 47 blood group systems containing more than 360 known blood antigens. These antigens are molecules found on the surface of red blood cells, and even tiny differences between donors and recipients can sometimes trigger severe immune reactions.
The newly recognized MAL blood group system centers on the AnWj antigen, a rare blood marker first identified in 1972. The name “AnWj” comes from the first patients found to produce the antibody, Anton and Wj.
For more than 50 years, researchers could detect the antigen but could not determine which gene created it.
A Medical Puzzle Finally Solved
Using whole exome sequencing, which analyzes all protein-coding regions of DNA, the team discovered that inherited AnWj-negative individuals carry deletions in both copies of the MAL gene.
That gene produces a small membrane protein called Mal, which plays roles in cell membrane stability and cellular transport. Researchers found that people with normal AnWj-positive blood express the full-length Mal protein on their red blood cells, while AnWj-negative individuals do not.
To confirm the finding, scientists inserted the normal MAL gene into blood cell lines in the lab. Those cells began producing the AnWj antigen. Mutated versions of the gene failed to do so, providing strong proof that the Mal protein is directly responsible for the blood group.
The work also demonstrated that Mal alone is enough to produce the AnWj antigen, resolving earlier theories that linked the blood type to other genes.
Why This Discovery Matters
The vast majority of people, more than 99.9%, are AnWj-positive. But for the tiny number who are AnWj-negative, receiving incompatible blood could trigger a serious transfusion reaction.
Until now, identifying these individuals has been extremely difficult because the genetic basis of the blood group was unknown.
The discovery means new genetic tests can now be developed to identify rare donors and patients before transfusions take place. Researchers say these tests could eventually be integrated into existing blood typing platforms.
This is especially important because many AnWj-negative cases are not inherited. Certain blood disorders and cancers can temporarily suppress the Mal protein, causing patients to appear AnWj-negative even though they do not carry the rare genetic form.
The inherited version itself appears to be extraordinarily uncommon. The study identified only five genetically AnWj-negative individuals, including members of an Arab-Israeli family. Researchers suspect there may be additional undiagnosed cases worldwide now that testing is possible.
Importantly, people born with the inherited MAL deletion are otherwise healthy.
A Discovery Decades in the Making
The breakthrough relied on advances in DNA sequencing technology that did not exist when the antigen was first discovered.
Louise Tilley, Senior Research Scientist at NHS Blood and Transplant, spent nearly two decades investigating the mystery.
“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,” Tilley said. “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.”
She added that the research was particularly difficult because inherited cases are so 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.”
Ash Toye, Professor of Cell Biology at the University of Bristol, said the discovery highlights how modern genetic tools are transforming transfusion medicine.
“It’s really exciting we were able use our ability to manipulate gene expression in the developing blood cells to help confirm the identity of the AnWj blood group, which has been an outstanding puzzle for half a century,” he said.
Nicole Thornton, Head of IBGRL Red Cell Reference at NHS Blood and Transplant, described the project as one of the organization’s most challenging investigations.
“There is so much work that goes into proving that a gene does actually encode a blood group antigen, but it is what we are passionate about, making these discoveries for the benefit of rare patients around the world,” Thornton said.
The discovery has now also been formally recognized by the International Society of Blood Transfusion (ISBT), which ratified MAL as the world’s 47th official blood group system.
Why Rare Blood Research Is Increasingly Important
Although rare blood types affect only a small number of people, identifying them has become increasingly important as medicine grows more personalized and globally connected.
Patients with uncommon blood groups often rely on specially matched donors, sometimes from entirely different countries. Blood banks worldwide maintain rare donor registries to help locate compatible blood during emergencies or complex medical treatments.
Researchers say discoveries like MAL continue to shrink the number of unexplained blood antigens left in medicine, improving both transfusion safety and understanding of human genetics.
Reference: “Deletions in the MAL gene result in loss of Mal protein, defining the rare inherited AnWj-negative blood group phenotype” by Louise A Tilley, Vanja Karamatic Crew, Tosti J Mankelow, Samah A AlSubhi, Benjamin Jones, Abigail Borowski, Vered Yahalom, Lilach Finkel, Belinda K Singleton, Piers J Walser, Ashley Mark Toye, Timothy J Satchwell, Nicole M Thornton, 18 August 2024, Blood.
DOI: 10.1182/blood.2024025099
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