The MAL Blood Group System: A Scientific Discovery Solves a Half-Century-Old Mystery

The MAL Blood Group System: A Scientific Discovery Solves a Half-Century-Old Mystery

Dr. Nahlan Juwair Hassan

20 -10- 2026

The discovery of the MAL blood group system is more than just the addition of a new name to the list of known blood groups; it is the solution to a medical mystery that began in 1972, when scientists discovered that the red blood cells of a pregnant woman lacked an antigen known as AnWj. Although laboratories were able to identify this rare condition, its genetic basis remained unknown for decades—until researchers finally identified the protein associated with the antigen and uncovered the role of the *MAL* gene in its expression [1, 2].

Why are the A, B, and O blood groups not enough?

Most people are familiar with the A, B, AB, and O blood groups, as well as the Rhesus (Rh) factor. However, these classifications represent only a fraction of the true complexity found on the surface of red blood cells. These cells carry hundreds of antigens that vary from person to person; the immune system can recognize some of these and produce antibodies against them.

If an individual receives blood containing an antigen they lack—and they possess antibodies directed against that antigen—an immune response may occur, leading to the destruction (hemolysis) of the transfused red blood cells, which can have serious consequences. Consequently, ensuring blood compatibility is far more complex than simply matching the ABO and Rh systems.

According to data from the International Society of Blood Transfusion (ISBT) as of June 2024, there are 47 recognized blood group systems, encompassing 366 distinct antigens. This highlights the vast extent of antigenic diversity in human blood [2, 3].

What is the AnWj antigen, and how does it relate to the Mal protein?

The AnWj antigen is a molecular marker typically found on the membrane of red blood cells. It is carried by a protein called Mal—a multi-pass membrane protein that spans the cell membrane—which is encoded by the *MAL* gene.

The significance of this discovery lies in the fact that the absence of a specific antigen does not necessarily imply a difference in conventional blood types; rather, it may reflect a variation in a different protein on the cell surface. Identifying the protein and gene associated with this antigen has enabled researchers to explain the phenomenon at a molecular level [1].

How was the mystery solved after more than fifty years?

The story began in 1972, when an unusual blood profile—characterized by the absence of the AnWj antigen—was discovered in a pregnant woman. While researchers were able to identify this condition using serological tests, they could not determine the underlying genetic cause.

In 2024, research findings published in the journal *Blood* revealed the genetic basis for this phenomenon. The researchers employed genetic sequencing techniques, including exome sequencing, to examine genes that could account for the absence of the antigen.

The results revealed deletions in the *MAL* gene in individuals who genetically lack the AnWj antigen. In the cases studied, these deletions involved the third and fourth exons, resulting in the absence of a functional Mal protein on the surface of the red blood cells. The researchers did not stop at establishing a genetic link; they also conducted further cellular and molecular experiments, including an analysis of protein expression in the cells under study. The results demonstrated that the Mal protein is essential for the presence of the AnWj antigen. Thus, the research progressed from the observation of a rare blood phenomenon to an explanation supported by both genetic and experimental evidence [1].

Does every individual who tests negative for the AnWj antigen carry a genetic alteration?

Not necessarily. It is important to distinguish between the genetic absence of the antigen and its acquired absence. While a genetic profile may involve deletions in the *MAL* gene, the expression of the antigen can also be suppressed in certain acquired cases associated with specific medical conditions.

Therefore, a negative serological result alone is insufficient to confirm the presence of a genetic alteration; further testing may be required to determine the underlying cause. Making this distinction helps ensure the accurate interpretation of blood test results and prevents the drawing of incorrect genetic conclusions [1, 2].

Medical Significance of the Discovery

The clinical significance of this discovery becomes apparent during blood transfusions for individuals who lack the AnWj antigen. If such an individual possesses antibodies directed against this antigen, the transfusion of AnWj-positive red blood cells could trigger a severe hemolytic reaction.

Understanding the genetic basis of the MAL system facilitates the development of genetic testing and improves the assessment of blood compatibility—particularly in rare cases where results from routine tests are difficult to interpret. It also enables reference immunohematology laboratories to characterize specific cases and select appropriate blood units when necessary.

However, the absence of the antigen does not automatically imply that a dangerous reaction will occur during a transfusion; the risk depends on the presence of relevant antibodies and the overall compatibility between the donor blood and the recipient [1, 2].

Recognition of the MAL System

In June 2024, the International Society of Blood Transfusion (ISBT) recognized the MAL system as the 47th human blood group system, with the AnWj antigen classified under it. This marked a significant milestone in categorizing human antigenic diversity and linking serological markers to their underlying molecular basis.

When citing these figures, it is essential to consider the specific timeframe; data from June 2024 identified 47 systems and 366 antigens, whereas the ISBT database—updated as of September 24, 2026—lists 49 systems and 400 antigens. This shift reflects the ongoing evolution of immunohematology and the continuous discovery of new blood group systems and antigens [2, 3]. Conclusion

The story of the MAL blood group system reveals a fundamental characteristic of scientific research: while clinicians may successfully identify a clinical phenomenon, its explanation can remain unknown for decades—until the appropriate molecular tools and experimental approaches become available. The journey began in 1972 with the observation that an antigen was absent from the red blood cells of a pregnant woman; it culminated in the identification of the Mal protein and the role of the *MAL* gene in the expression of the AnWj antigen, ultimately leading to the recognition of a new blood group system in 2024.

The true significance of this discovery lies not merely in adding a new entry to the list of blood group systems, but in bridging the gap between clinical observation and molecular genetics. It transforms fundamental knowledge into a practical tool for enhancing blood compatibility and reducing the risks associated with incompatible blood transfusions. This serves as a clear illustration of how an understanding of minute molecular details can be critical to clinical medicine.

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