New MAL Blood Group Discovered: How a 50-Year Mystery Could Make Blood Transfusions Safer

Scientists have solved a 50-year mystery surrounding a rare human blood marker, identifying the genetic basis of the AnWj antigen and establishing MAL as a new blood group system.

The breakthrough, announced by researchers at NHS Blood and Transplant and the University of Bristol, traces a mystery first identified in 1972 to the MAL gene and could help doctors identify rare patients who may be at risk of transfusion reactions.

The discovery matters because blood matching involves far more than the familiar A, B, AB, O and Rh groups. Red blood cells carry hundreds of surface markers, known as antigens. While most do not cause problems during routine transfusions, an unusual antigen difference can become critical when a patient has antibodies that react against donated blood.

What is the New MAL blood group?

The AnWj antigen was first discovered in 1972, but researchers could not determine which gene or protein was responsible for producing it on red blood cells.

That changed when scientists used whole exome sequencing, a technique that examines the protein-coding sections of DNA. Their analysis pointed to the MAL gene. Researchers found that people with the rare inherited AnWj-negative blood type had deletions affecting both copies of the gene.

The MAL gene produces a small protein called Mal. Researchers found that AnWj-positive people had the full-length Mal protein on their red blood cells, while it was absent from cells from AnWj-negative individuals.

More than 99.9% of people are AnWj-positive, meaning the inherited AnWj-negative type is exceptionally rare. Only five genetically AnWj-negative people were included in the investigation, including members of an Arab Israeli family.

Why can a rare blood marker matter?

For most people, AnWj status does not create an everyday health concern. The issue becomes important when an AnWj-negative person has antibodies against the antigen and receives AnWj-positive blood.

Those antibodies can attack the transfused red blood cells and potentially cause a serious transfusion reaction.

There is also an important distinction between inherited and acquired AnWj-negative status. Most people who lack detectable AnWj expression do so because of an underlying blood disorder or certain cancers that suppress the antigen. Only a very small number are born with the inherited genetic form linked to MAL.

How did scientists prove MAL was responsible?

Finding a genetic link was not enough. The researchers needed to show that Mal actually carried the AnWj antigen.

They introduced a normal MAL gene into laboratory cells. Those cells then reacted with AnWj antibodies, while cells carrying the altered gene did not show the same response. This provided evidence that Mal was responsible for the antigen.

Louise Tilley, senior research scientist at the International Blood Group Reference Laboratory at NHS Blood and Transplant, said the genetic background of AnWj had remained a mystery for more than five decades.

“It represents a huge achievement, and the culmination of a long team effort,” Tilley said.

Ash Toye, professor of cell biology at the University of Bristol, said manipulating gene expression helped confirm the identity of the blood group.

“This development will help identify these rare donors and help patients in the future,” Toye said.

What changes for patients?

The most immediate benefit is the possibility of genetic testing for rare AnWj-negative patients and donors.

Researchers say genotyping tests can now be developed to detect inherited MAL changes and potentially added to existing blood-group testing systems. That could make it easier for blood specialists to identify compatible donors before a transfusion becomes urgent.

Nicole Thornton, head of the IBGRL Red Cell Reference at NHS Blood and Transplant, said the discovery enables such testing to be integrated into existing systems.

“Now genotyping tests can be designed to identify genetically AnWj-negative patients and donors,” Thornton said.

The MAL discovery therefore does not mean most people need to worry about their blood type. Instead, it gives doctors a clearer genetic tool for finding a very small group of patients for whom an uncommon blood marker could become critically important during transfusion. It also shows how much remains to be understood beyond the blood groups people commonly associate with A, B, AB, and O.