Role of MRP4 (ABCC4) in platelet adenine nucleotide-storage: evidence from patients with delta-storage pool deficiencies.
We previously showed that the MRP4 (ABCC4) transporter is expressed in human platelet delta-granules and may be involved in ADP transport. We now demonstrate by immunoblotting and immunofluorescence microscopy that platelet MRP4 is absent in two patients with a platelet delta-storage pool deficiency (delta-SPD)-like phenotype with reduced platelet adenine nucleotide (AN) but normal serotonin levels, whereas their other membrane marker proteins of platelet granules were normally expressed and localized. In these patients, MRP4 was present in lymphocytes, and the coding region of their MRP4/ABCC4 gene did not show any mutation that explained the lack of expression. In platelets with "classic" delta-SPD (low AN and serotonin levels), MRP4 was quantitatively (immunoblot) normal, but, like other delta-granules membrane marker proteins (eg, LAMP2), was mostly displaced from delta-granules to patches at the plasma membrane, suggesting that platelets with classic delta-SPD have an abnormality that impairs the assembly of normal delta-granules. Thus, defective expression of platelet MRP4 is associated with selective defect in AN storage. The genetic basis of the new delta-SPD phenotype remains to be elucidated.
Jedlitschky
Gabriele
G
Department of Pharmacology, Research Center of Pharmacology and Experimental Therapeutics, Institut für Pharmakologie, Ernst-Moritz-Arndt-University, Friedrich-Loeffler-Str. 23d, D-17487, Greifswald, Germany. jedlits@uni-greifswald.de
Cattaneo
Marco
M
Lubenow
Lena E
LE
Rosskopf
Dieter
D
Lecchi
Anna
A
Artoni
Andrea
A
Motta
Giovanna
G
Niessen
Juliane
J
Kroemer
Heyo K
HK
Greinacher
Andreas
A
D000227:Adenine Nucleotides / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D001792:Blood Platelets / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010979:Platelet Function Tests; D010981:Platelet Storage Pool Deficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D000227:Adenine Nucleotides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C073492:ABCC4 protein, human