Article Impact Level: HIGH Data Quality: STRONG Summary of Blood Journal, blood.2024025099. https://doi.org/10.1182/blood.2024025099 Dr. Louise A Tilley et al.
Points
- The AnWj-negative blood group phenotype is caused by a deletion in the MAL gene, which encodes the Mal protein, crucial for AnWj antigen expression.
- Previous studies linked the AnWj antigen to the CD44 and Smyd1 proteins but failed to provide conclusive evidence; this study found no shared mutations in those genes.
- Whole exome sequencing revealed a large deletion in MAL among AnWj-negative individuals, confirming it as the genetic determinant for the blood group.
- Mal protein is absent in AnWj-negative individuals, and anti-AnWj antibodies specifically target Mal, linking it directly to AnWj antigen expression.
- Overexpression of MAL in an erythroid cell line induced AnWj antigen expression, establishing that Mal is both necessary and sufficient for its presence. Thus, this resolves a longstanding genetic mystery.
Summary
This study identifies the genetic cause of the rare inherited AnWj-negative blood group phenotype, revealing that it is due to homozygosity for a deletion in the MAL gene, which encodes Myelin and lymphocyte protein (Mal). The AnWj antigen has been of interest since 1972, with previous studies suggesting links to the CD44 and Smyd1 proteins, but without conclusive results. In this study, whole exome sequencing of individuals with the inherited AnWj-negative phenotype revealed no shared mutations in CD44H or SMYD1 but uncovered a common large deletion in MAL. Further confirmation of this deletion was observed in unrelated AnWj-negative individuals, establishing MAL as the genetic determinant of the AnWj-negative blood group.
Mal protein, expressed on the red blood cell membranes of AnWj-positive individuals, was absent in inherited and suppressed cases of AnWj-negative individuals. This study further demonstrated that anti-AnWj antibodies specifically target the Mal protein, as anti-AnWj could inhibit anti-Mal binding in AnWj-positive red blood cells. This finding directly links the presence of Mal protein to the AnWj antigen expression, providing a molecular explanation for the AnWj-negative phenotype.
Additionally, overexpression of MAL in an erythroid cell line induced the expression of AnWj antigen, regardless of CD44 presence. This demonstrated that Mal is both necessary and sufficient for AnWj antigen expression. The results provide crucial insight into the genetic basis of the AnWj-negative phenotype, resolving a long-standing mystery and establishing the foundation for a new blood group system, significantly reducing the number of unresolved antigens.
Link to the article: https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2024025099/517404/Deletions-in-the-MAL-gene-result-in-loss-of-Mal
References Tilley, L. A., Karamatic Crew, V., Mankelow, T. J., AlSubhi, S. A., Jones, B., Borowski, A., Yahalom, V., Finkel, L., Singleton, B. K., Walser, P. J., Toye, A. M., Satchwell, T. J., & Thornton, N. M. (2024). Deletions in the MAL gene result in loss of Mal protein, defining the rare inherited AnWj-negative blood group phenotype. Blood Journal, blood.2024025099. https://doi.org/10.1182/blood.2024025099
