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

Slim Azouzi (1, 2, 3, 4) , Mahmoud Mikdar (1, 2, 3, 4) , Patricia Hermand (1, 2, 3) , Emilie-Fleur Gautier (5, 1) , Virginie Salnot (5, 1) , Alexandra Willemetz (1, 2, 3, 4) , Gaël Nicolas (1, 6) , Cedric Vrignaud (1, 2, 3, 4) , Alexandre Raneri (3, 1) , Patrick Mayeux (5, 1) , Christine Bole-Feysot (7) , Patrick Nitschké (7) , Jean-Pierre Cartron (3) , Yves Colin (2, 3, 1) , Olivier Hermine (8) , Gabriele Jedlitschky (9) , Marc Cloutier (10) , Jessica Constanzo-Yanez (11) , Carole Ethier (10) , Nancy Robitaille (11) , Maryse St-Louis (10) , Caroline Le van Kim (2, 3, 1) , Thierry Peyrard (2, 3, 1, 4)

1 Labex Gr-Ex - Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge
2 BIGR (UMR_S_1134 / U1134) - Biologie Intégrée du Globule Rouge
3 INTS - Institut National de la Transfusion Sanguine [Paris]
4 Département Centre National de Référence pour les Groupes Sanguins [Paris]
5 3P5 - Plateforme protéomique 3P5 [Institut Cochin]
6 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
7 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
8 CHRI - Cytokines, hématopoïèse et réponse immune
9 University of Medicine Greifswald
10 Héma-Québec [Québec]
11 Héma-Québec [Montréal]

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.

Domaines: Sciences du Vivant [q-bio]

Slim Azouzi, Mahmoud Mikdar, Patricia Hermand, Emilie-Fleur Gautier, Virginie Salnot, et al.. Lack of the multidrug transporter MRP4/ABCC4 defines the PEL-negative blood group and impairs platelet aggregation. Blood, 2019, 135 (6), pp.441-448. ⟨10.1182/blood.2019002320⟩. ⟨hal-02416860⟩