The breakthrough discovery of a new blood group, MAL, has finally unraveled a 50-year-old mystery. A team of researchers from NHS Blood and Transplant (Bristol), NHSBT’s International Blood Group Reference Laboratory (IBGRL), and the University of Bristol have successfully identified the genetic background of the elusive AnWj blood group antigen. This significant finding will greatly aid in the identification and treatment of rare patients lacking this blood group.
While some individuals may lack this blood group due to illness, the inherited form of the AnWj-negative phenotype has only been observed in a small number of people. Thanks to this discovery, it will be easier to identify and assist others with this rare blood group in the future.
The ABO and Rh blood group systems are well-known, but the complexity of Blood goes beyond these two systems. Matching Blood across other groups can be crucial for saving lives.
Receiving AnWj-positive Blood can cause a transfusion reaction in people who are AnWj-negative. The latest research is paving the way for developing new genotyping tests to identify these rare individuals, ultimately reducing the risk of transfusion-associated complications.
Discovered in 1972, the AnWj antigen’s genetic background remained unknown until now. Recently, a breakthrough study to be published in Blood, the journal of the American Society of Hematology and currently available online in pre-print, has revealed that the AnWj antigen belongs to a new blood group system (MAL) – the 47th to ever be identified.
The research team has discovered that AnWj is carried on the Mal protein. Over 99.9% of people are AnWj-positive and exhibit full-length Mal protein expression on their red cells, which is not present in AnWj-negative individuals. Homozygous deletions in the MAL gene have been linked to the inherited AnWj-negative phenotype.
The primary cause of being AnWj-negative is attributed to hematological disorders or certain types of cancer that suppress antigen expression. A small number of individuals are genetically AnWj-negative, with the study identifying five such individuals, including a family of Arab-Israelis. In 2015, a blood sample was taken from a lady who was the first AnWj-negative person discovered in the 1970s.
The research team employed whole exome sequencing, which entails the genetic sequencing of all DNA that encodes proteins. This method revealed that these rare inherited cases stemmed from homozygous DNA sequence deletions in the MAL gene, which is responsible for the Mal protein.
The evidence that Mal is responsible for the binding of AnWj antibodies found in these rare patients was substantiated by experiments demonstrating specific reactivity in cells where the normal MAL gene was introduced, but not in those where the mutant gene was introduced.
“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,” said Louise Tilley, Senior Research Scientist, IBGRL Red Cell Reference at NHS Blood and Transplant.
“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.”
“It’s really exciting we were able to 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. This development will help identify these rare donors and help patients in the future,” said Ash Toye, Professor of Cell Biology in the School of Biochemistry and Director of the NIHR Blood and Transplant Research Unit in red cell products at the University of Bristol.
“Resolving the genetic basis for AnWj has been one of our most challenging projects,” said Nicole Thornton, Head of IBGRL Red Cell Reference at NHS Blood and Transplant. “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. Now, genotyping tests can be designed to identify genetically AnWj-negative patients and donors. Such tests can be added to the existing genotyping platforms.”
Dr Tim Satchwell, Senior Lecturer at UWE Bristol, who contributed to the study whilst a Research Fellow at the University of Bristol, said: “Mal is a very small protein with some interesting properties which made it difficult to identify and meant we needed to pursue multiple lines of investigation to accumulate the proof we needed to establish this blood group system. Being able to combine our expertise to finally achieve this has brought the whole team a lot of satisfaction.”
Journal reference:
- 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. Deletions in the MAL gene result in loss of Mal protein, defining the rare inherited AnWj-negative blood group phenotype. Blood, 2024; DOI: 10.1182/blood.2024025099
