A team of researchers has made a significant breakthrough in the field of transfusion medicine by identifying a new blood group system, called MAL. This discovery, published in the journal Blood by the American Society of Hematology, solves the mystery surrounding the AnWj antigen, a marker on the surface of red blood cells whose genetic origin had been unknown for more than five decades.

Although the most well-known blood group systems are ABO and Rh, the landscape is much more complex. Numerous antigens exist on the surface of red blood cells and must be considered during transfusions, as an incorrect combination can trigger severe reactions in patients.

The new MAL system is the 47th to be discovered, and its significance lies in the potential to prevent adverse reactions in people with a rare phenotype known as AnWj-negative. Individuals who lack this antigen on the surface of their red blood cells, due to a genetic mutation or disease, may experience serious complications if they receive AnWj-positive blood.

A Breakthrough After 50 Years of Mystery

The AnWj antigen was first identified in 1972, but its genetic origin remained a mystery. After years of research, the team led by the UK’s National Health Service Blood and Transplant (NHS Blood and Transplant) and the International Blood Group Reference Laboratory (IBGRL) has demonstrated that the AnWj antigen is related to the Mal protein, present in more than 99.9% of the global population. In individuals with the AnWj-negative phenotype, this protein is absent due to a homozygous deletion in the MAL gene, which encodes this protein.

This discovery has crucial implications for developing new genetic tests that can detect individuals with this rare phenotype before undergoing a transfusion. In the past, the most common cause of AnWj absence was a hematological disorder or certain types of cancer that suppressed the antigen’s expression. However, only an extremely small number of people have the inherited genetic variant that results in the absence of the AnWj antigen.

During the study, five individuals with the inherited form of the AnWj-negative phenotype were identified, including an Arab-Israeli family, as well as a unique case of a woman whose blood type was first detected in the 1970s.

This breakthrough was achieved thanks to whole-exome sequencing, a technique that allows researchers to study all the protein-coding regions of DNA. This methodology was key to identifying deletions in the MAL gene that cause the inherited AnWj-negative phenotype. The scientific team also demonstrated that the Mal protein is responsible for the binding of AnWj antibodies, confirming its role in this new blood group system.

The ability to manipulate gene expression in developing blood cells allowed researchers to verify their findings. This innovation is critical, as it will facilitate the identification of donors with the AnWj-negative phenotype, helping improve transfusion safety for these patients.

Louise Tilley, a research scientist at IBGRL, highlighted that solving the genetic mystery behind the AnWj antigen has been one of the most important achievements of her career. The complexity of the work lay in the rarity of the genetic cases. Without exome sequencing, we wouldn’t have been able to identify the responsible gene, as MAL wasn’t an obvious candidate, Tilley noted, also expressing her gratitude to the patients and other researchers involved in this extensive effort.

Meanwhile, Professor Ash Toye from the University of Bristol praised the team’s ability to manipulate gene expression and solve a mystery that had remained unanswered for over half a century. This breakthrough not only represents a significant scientific contribution but also a key tool to improve the treatment of patients with special blood needs.

SOURCES

University of Bristol

Louise A Tilley, Vanja Karamatic Crew, et al., Deletions in the MAL gene result in loss of Mal protein, defining the rare inherited AnWj-negative blood group phenotype. Blood 2024; blood.2024025099. doi.org/10.1182/blood.2024025099

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