Lack of the multidrug transporter MRP4/ABCC4 defines the PEL-negative blood group and impairs platelet aggregation
Year: 2019
Type: article
Abstract: 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.
Source: Blood
Authors: 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
Institutions: Inserm, Université Paris Cité, Institut National de la Transfusion Sanguine, Laboratory of Excellence GR-Ex, Biologie intégrée du globule rouge et de l'Erythropoïèse, Centre National de la Recherche Scientifique, Institut Cochin, Centre de Recherche sur l'Inflammation, Institut des Maladies Génétiques Imagine, Universitätsmedizin Greifswald, Universität Greifswald, Héma-Québec
Language: English
Topic: Blood groups and transfusion
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2995207676