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New Blood Group System Discovered After Decades-Old Mystery Solved

A rare genetic anomaly first identified over 50 years ago has led to the official recognition of a new blood group system, named MAL. The breakthrough, achieved through a collaborative effort between scientists in Israel and the United Kingdom, helps explain the absence of a common blood antigen—AnWj—in a tiny fraction of the global population.

The story began in 1972 when doctors encountered a pregnant woman whose blood sample lacked a molecule typically found in over 99.9% of people. The missing antigen, later identified as AnWj, appears on red blood cells and normally develops a few days after birth. Its absence puzzled researchers for decades, until a recent study published in the journal Blood offered conclusive answers.

The study revealed that individuals who do not express the AnWj antigen have a homozygous deletion in both copies of the MAL gene. This genetic change prevents the production of the MAL protein—a small membrane-bound molecule essential for maintaining cell membrane stability and regulating intracellular processes.

Dr. Vered Yahalom, director of the Blood Services and Apheresis Unit at Beilinson Hospital and a co-author of the study, recalls first encountering such a case in 1988. A woman from the Wadi Ara region in northern Israel showed an unusual reaction: her plasma responded to all rare blood cell samples and all available antisera, suggesting she carried an antibody targeting a highly prevalent antigen.

Subsequent testing revealed that her blood did not react with the known anti-Wj antibody, pointing instead to a reaction against AnWj—an antigen only documented in scientific literature since the early 1970s. Over the years, more members of her extended family across two additional generations were found to share the same rare phenotype, all without signs of illness.

Researchers in the UK’s IBGRL laboratory performed whole exome sequencing on individuals with the AnWj-negative phenotype and found identical deletions in exons 3 and 4 of the MAL gene. When scientists introduced a healthy version of the gene into cells lacking the antigen, the AnWj protein was expressed—proving that the MAL protein alone is sufficient to produce the antigen.

Moreover, the study confirmed that anti-AnWj antibodies and anti-MAL antibodies bind to the same molecular site, cementing the relationship between the gene and the newly classified antigen. In 2024, the International Society of Blood Transfusion (ISBT) officially recognized MAL as a new, independent blood group system.

Dr. Ariel Aviv, head of the hematology unit at HaEmek Medical Center, emphasized the clinical significance of this discovery. Not only can this genetic trait now be identified in prenatal testing, but it also enhances our understanding of how red blood cells interact with the immune system. He added that the small MAL protein may have additional roles yet to be explored.

Dr. Tim Satchwell, a cell biologist from the University of the West of England, noted that MAL’s minuscule size and unique properties made it difficult to detect. The team had to follow several research paths in parallel to gather enough evidence.

One major medical implication involves transfusions. Patients with anti-AnWj antibodies are at risk of severe immune reactions if given mismatched blood. Accurate identification of this condition is crucial to ensure safe blood matching and avoid complications.

“This is a testament to the power of international collaboration,” said Dr. Yahalom. “Not only does it help us locate rare donors and tailor transfusions, but it also deepens our understanding of human biology in ways we couldn’t have imagined decades ago.”

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