Scientists Identify the New MAL Blood Group System After 50 Years

A newly identified MAL blood group system

In 1972, doctors took a blood sample from a pregnant woman and found that it lacked a surface molecule present on every other red blood cell known at the time.

Five decades later, that unusual molecular omission enabled researchers in the UK and Israel to define a previously unknown human blood group system. The team published its findings in 2024.

"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 UK National Health Service haematologist Louise Tilley last September, following almost 20 years spent personally investigating this blood-related anomaly.

Although the ABO blood group system and the Rh factor - the plus or minus designation - are the systems most people know, humans have numerous blood group systems. These depend on the diverse proteins and sugars found on the surfaces of blood cells.

As well as serving other functions, these antigen molecules act as identity labels, allowing the body to distinguish 'self' from potentially dangerous foreign cells. If the markers are incompatible during a blood transfusion, a treatment intended to save a life can trigger reactions and may even prove fatal.

AnWj antigen and the rare MAL blood type

Most major blood groups were recognised during the early 20th century. Many systems identified since then, including the Er blood system first reported by researchers in 2022, affect only a small number of people. The newly recognised blood group is similarly rare.

"The work was difficult because the genetic cases are very rare," Tilley explained.

Earlier research showed that more than 99.9 percent of people carry the AnWj antigen missing from the 1972 patient's blood. The antigen is found on a myelin and lymphocyte protein, so the researchers named the newly described system the MAL blood group.

People with a mutated version of both copies of their MAL genes develop an AnWj-negative blood type, as the pregnant patient did. Tilley and her colleagues also identified three people with this rare blood type who did not have the mutation, indicating that blood disorders can sometimes suppress the antigen as well.

"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," explained University of the West of England cell biologist Tim Satchwell.

Confirming the MAL gene mutation

After decades of investigation, the researchers confirmed they had identified the right gene by introducing the normal MAL gene into AnWj-negative blood cells. This caused those cells to produce the AnWj antigen.

The MAL protein is already known to have an essential role in maintaining stable cell membranes and helping with cell transport. Previous work has also shown that AnWj is not present in newborn babies, appearing shortly after birth instead.

Notably, every AnWj-negative patient in the study had the same mutation. Yet researchers found no other cell abnormalities or diseases linked to it.

With the genetic markers responsible for the MAL mutation now identified, patients can be tested to establish whether their negative MAL blood type is inherited or results from antigen suppression, which may indicate another underlying medical condition.

These uncommon blood variations can have severe consequences for patients. Understanding more of them could therefore help save more lives.

The research was published in Blood.

An earlier version of this article was published in September 2024.