Researchers Discover New Blood Group System

The discovery of a new blood group, MAL, has helped solve a 50-year-old mystery. Researchers from NHS Blood and Transplant (Bristol), the NHSBT International Blood Group Reference Laboratory (IBGRL) and the University of Bristol have identified the genetic background of the previously known but mysterious blood group antigen AnWj. These findings provide insight into the identification and treatment of the rare patients without this blood group.

Some people may not have this blood type due to the effect of a disease, but the rare hereditary form of the AnWj-negative phenotype has only been found in a handful of individuals – although thanks to this discovery, it will now be easier to find more in the future.

The two most well-known blood group systems are ABO and Rh, but blood is more complex and matching other groups can save lives.

If AnWj-negative individuals receive AnWj-positive blood, they could have a transfusion reaction, and this research is enabling the development of new genotyping tests to detect these rare individuals and reduce the risk of transfusion-associated complications.

The AnWj antigen, an antigen that is a surface marker, was discovered in 1972, but its genetic background was until now unknown. The new research, published in Bloodestablishes a new blood group system (MAL), the 47th ever discovered, as the focus of the AnWj antigen.

The research team established that AnWj is carried by the Mal protein. More than 99.9% of people are AnWj positive and these individuals were shown to express the full-length Mal protein on their red blood cells, which was not present on the cells of AnWj negative individuals. The team identified homozygous deletions in the MAL gene associated with the inherited AnWj negative phenotype.

The most common reason for an AnWj-negative gene to be present is the presence of a blood disorder or certain types of cancer that suppress the expression of the antigens. Only a very small number of people are AnWj-negative due to a genetic cause. Five AnWj-negative individuals participated in the study, including a family of Israeli Arabs. The blood tested included a sample donated by a woman in 2015, who was the first AnWj-negative person to be discovered in the 1970s.

The research team used whole-exome sequencing (the genetic sequencing of all the DNA that codes for proteins) to show that these rare hereditary cases were caused by homozygous deletions of DNA sequences in the MAL gene, which codes for the Mal protein.

Evidence that Mal is responsible for binding AnWj antibodies isolated from these rare patients was provided by experiments showing the appearance of specific reactivity with cells into which the researchers introduced the normal MAL gene but not the mutant gene.

Louise Tilley, Principal Investigator in the IBGRL Red Blood Cell Reference Service at NHS Blood and Transplant, said: “The genetic background to AnWj has been a mystery for over 50 years, and it’s one that I have personally been trying to solve for nearly 20 years of my career. This is 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.”

“The work has been difficult because genetic cases are very rare. We would not have achieved this without exome sequencing, as the gene we identified was not an obvious candidate and little is known about the Mal protein in red blood cells. Proving our results has been a challenge and we thank all our collaborators and patients for their help, without whom we would not have reached this point.”

Ash Toye, Professor of Cell Biology in the School of Biochemistry and Director of the NIHR Blood and Transplant Products Research Unit at the University of Bristol, said: “It is really exciting that we have been able to use our ability to manipulate gene expression in developing blood cells to help confirm the identity of the AnWj blood group, which has been a major enigma for half a century. This development will help identify these rare donors and help patients in the future.”

Nicole Thornton, IBGRL Red Blood Cell Reference Service Manager at NHS Blood and Transplant, said: “Solving the genetic basis of AnWj has been one of our most challenging projects.

“There is so much work to be done to prove that a gene actually codes for a blood group antigen, but that’s what we’re passionate about, making these discoveries for the benefit of rare patients around the world.

“Genotyping tests can now be designed to identify patients and donors who are genetically negative for AnWj. Such tests can be added to existing genotyping platforms.”

Dr Tim Satchwell, a lecturer at UWE Bristol, who contributed to the study while he was a researcher at the University of Bristol, said: “Mal is a very small protein with interesting properties that make it difficult to identify and require us to pursue several lines of research to build up the evidence needed to establish this blood group system. Being able to combine our expertise to finally achieve this has been very rewarding for the whole team.”