Lack of the multidrug transporter MRP4/ABCC4 defines the PEL-negative blood group and impairs platelet aggregation.

The rare PEL-negative phenotype is one of the last blood groups with an unknown genetic basis. By combining whole-exome sequencing and comparative global proteomic investigations, we found a large deletion in the ABCC4/MRP4 gene encoding an ATP-binding cassette (ABC) transporter in PEL-negative individuals. The loss of PEL expression on ABCC4-CRISPR-Cas9 K562 cells and its overexpression in ABCC4-transfected cells provided evidence that ABCC4 is the gene underlying the PEL blood group antigen. Although ABCC4 is an important cyclic nucleotide exporter, red blood cells from ABCC4null/PEL-negative individuals exhibited a normal guanosine 3',5'-cyclic monophosphate level, suggesting a compensatory mechanism by other erythroid ABC transporters. Interestingly, PEL-negative individuals showed an impaired platelet aggregation, confirming a role for ABCC4 in platelet function. Finally, we showed that loss-of-function mutations in the ABCC4 gene, associated with leukemia outcome, altered the expression of the PEL antigen. In addition to ABCC4 genotyping, PEL phenotyping could open a new way toward drug dose adjustment for leukemia treatment. © 2020 by The American Society of Hematology.

Citation

Slim Azouzi, Mahmoud Mikdar, Patricia Hermand, Emilie-Fleur Gautier, Virginie Salnot, Alexandra Willemetz, Gaël Nicolas, Cédric Vrignaud, Alexandre Raneri, Patrick Mayeux, Christine Bole-Feysot, Patrick Nitschké, Jean-Pierre Cartron, Yves Colin, Olivier Hermine, Gabriele Jedlitschky, Marc Cloutier, Jessica Constanzo-Yanez, Carole Ethier, Nancy Robitaille, Maryse St-Louis, Caroline Le Van Kim, Thierry Peyrard. Lack of the multidrug transporter MRP4/ABCC4 defines the PEL-negative blood group and impairs platelet aggregation. Blood. 2020 Feb 06;135(6):441-448

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PMID: 31826245

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