András Váradi, PhD, DSc


Andras Varadi, PhD, DScHead of the Laboratory of Active Transport Proteins
Institute of Enzymology
Hungarian Academy of Sciences, Budapest, Hungary


In 1989, András Váradi organized his own research group in the Institute of Enzymology where the research interest of the group is the molecular mechanism of active transport proteins. First, they cloned and sequenced the cDNA followed by the complete gene of the organellar-type Ca-ATPase of Drosophila melanogaster. They also determined its tissue-specific expression pattern. The group then started to investigate the molecular mechanism of human multidrug ABC-transporter (e.g. MDR1 multi-drug resistance protein or P-glycoprotein) and to study the membrane topology and functional domains of the second multidrug transporter, MRP1. They targeted mutations in the ATP-utilization sites, in sites thought to be involved in drug recognition, in the phosphorylated linker segment, and in regions supposed to be responsible for intramolecular transduction. The group also elaborated knowledge of the membrane topology of ABCC1/MRP1, and identified its intracellular regulatory domain.

In 2001, András initiated a project to study the function of ABCC6 protein, in which the mutations are associated with pseudoxanthoma elasticum. They expressed the protein, the very first time, and demonstrated its ATP-dependent transport activity and showed that loss of activity is the cause of PXE in the case of certain mutants. András´ group published the first study on the transcriptional regulation of the human ABCC6 gene.

András was invited to be a plenary speaker at the FEBS Special Meeting on ABC Proteins, in Innsbruck (Austria) in 2006 and in 2008, and at the Gordon Research Conference “Elastin and Elastic Fibers” in 2005. András´ laboratory is a founding member of the EUROPXE Consortium, a European PXE research network established in 2007.  András organized together with S. Terry and J. Uitto a Satellite Symposium on Pseudoxanthoma Elasticum at the ESDR Annual Meeting, Budapest in 2009.  He teaches human molecular genetics and molecular biology at two major Budapest universities and supervises the projects of graduate students in the Laboratory. In 2013 András was elected to be a member of Academia Europaea.

Read an interview with András from April 2011.

PXE International 2014 Science Award.
 


Areas of Interest


ABCC6 ProteinAssay DevelopmentPXE and the Metabolism

 


Publications


Jansen RS, Duijst S, Mahakena S, Sommer D, Szeri F, Váradi A, Plomp A, Bergen AA, Elferink RP, Borst P, van de Wetering K. ATP-binding cassette subfamily C member 6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation. Arterioscler Thromb Vasc Biol. 2014 Jun 26. pii: ATVBAHA.114.304017. [epub ahead of print]. PMID: 24969777

Pomozi V, Brampton C, Fülöp K, Chen LH, Apana A, Li Q, Uitto J, Le Saux O, Váradi A. Analysis of pseudoxanthoma elasticum-causing missense mutants of ABCC6 in vivo: pharmacological correction of the mislocalized proteins. J Invest Dermatol. 2014 Apr;134(4):946-53. PMID: 24352041

Brampton C, Aherrahrou Z, Chen LH, Martin L, Bergen AA, Gorgels TG, Erdfdi J, Schunkert H, Szabó Z,Váradi A, Le Saux O. The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury. Am J Pathol. 2014 Jan;184(1):159-70. PMID: 24479134

Uitto J, Váradi A, Bercovitch L, Terry PF, Terry SF. Pseudoxanthoma elasticum: Progress in research toward treatment: Summary of the 2012 PXE International research meeting. J Invest Dermatol. 2013 Jun;133(6):1444-9. Free article at Journal Website. PMID: 23673496

Pomozi V, Le Saux O, Brampton C, Apana A, Iliás A, Szeri F, Martin L, Monostory K, Paku S, Sarkadi B, Szakács G, Váradi A. ABCC6 is a basolateral plasma membrane protein. Circ Res. 2013 May 24;112(11):e148-51. Free article in PubMed. PMID: 23625951

Arányi T, Bacquet C, de Boussac H, Ratajewski M, Pomozi V, Fülöp K, Brampton CN, Pulaski L, Le Saux O, Váradi A. Transcriptional regulation of the ABCC6 gene and the background of impaired function of missense disease-causing mutations. Front Genet. 2013;4:27. Free article in PubMed. PMID: 23483032

Le Saux O, Martin L, Aherrahrou Z, Lefthériotis G, Váradi A, Brampton CN. The molecular and physiological roles of ABCC6: more than meets the eye. Front Genet. 2012 Dec 12;3:289. Free article in PubMed. PMID: 23248644

Ratajewski M, de Boussac H, Sachrajda I, Bacquet C, Kovacs T, Váradi A, Pulaski L, Arányi T. ABCC6 expression is regulated by CCAAT/enhancer-binding protein activating a primate-specific sequence located in the first intron of the gene. J  Invest Dermatol. 2012 Dec;132(12):2709-17. Free article in PubMed. PMID: 22763786

Fülöp K, Jiang Q, Wetering KV, Pomozi V, Szabó PT, Arányi T, Sarkadi B, Borst P, Uitto J, Váradi A. ABCC6 does not transport vitamin K3-glutathione conjugate from the liver: relevance to pathomechanisms of pseudoxanthoma elasticum. Biochem Biophys Res Commun. 2011 Nov 25;415(3):468-71. Free article in PubMed. PMID: 22056557

Szabó Z, Váradi A, Li Q., Uitto J. ABCC6 does not transport adenosine - Relevance to pathomechanism of pseudoxanthoma elasticum. Mol Genet Metab. 2011 Nov;104(3):421. PMID: 21813308

Le Saux O, Fülöp K, Yamaguchi Y, Iliás A, Szabó Z, Brampton CN, Pomozi V, Huszár K, Arányi T, Váradi A. Expression and in vivo rescue of human ABCC6 disease-causing mutants in mouse liver. PLoS One. 2011;6(9):e24738. Published online 2011 Sep;6(9):e24738. Free article in PubMed. PMID: 21935449

Brampton C, Yamaguchi Y, Vanakker O, Van Laer L, Chen Lh, Thakore M, De Paepe A, Pomozi V, Szabó Pt, Martin L, Váradi A, Le Saux O. Vitamin K does not prevent soft tissue mineralization in a mouse model of pseudoxanthoma elasticum. Cell Cycle. 2011 Jun 1;10(11):1810-20. Free article in PubMed. PMID: 21597330

Váradi A, Szabo Z., Pomozi V, De Boussac H, Fulop K., Arányi T. Abcc6 as a target In pseudoxanthoma elasticum. Curr Drug Targets. 2011 May;12(5):671-82. Free article in PubMed. PMID: 21039331

Li Q, Sadowski S, Frank M, Chai C, Varadi A, Ho S, Lou H, Dean M, Thisse B, Uitto J. The abcc6a gene is required for normal zebrafish development. J Invest Dermatol. 2010 Nov;130(11):2561-8. Free article in PubMed. PMID: 20596085

de Boussac H, Ratajewski M, Sachrajda I, Köblös G, Tordai A, Pulaski L, Buday L, Váradi A, Arányi T. The ERK1/2-hepatocyte nuclear factor 4alpha axis regulates human ABCC6 gene expression in hepatocytes. J Biol Chem. 2010 Jul;285(30):22800-8. Free article in PubMed. PMID: 20463007

Köblös G, Andrikovics H, Prohászka Z, Tordai A, Váradi A, Arányi T. The R1141X loss-of-function mutation of the ABCC6 gene is a strong genetic risk factor for coronary artery disease. Genet Test Mol Biomarkers. 2010 Feb;14(1):75-8. Free article in PubMed. PMID: 19929409

Fülöp K, Barna L, Symmons O, Závodszky P, Váradi A. Clustering of disease-causing mutations on the domain-domain interfaces of ABCC6. Biochem Biophys Res Commun. 2009 Feb 13;379(3):706-9. PMID: 19133228

Li Q, Jiang Q, Pfendner E, Váradi A, Uitto J. Pseudoxanthoma elasticum: clinical phenotypes, molecular genetics and putative pathomechanisms. Exp Dermatol. 2009 Jan;18(1):1-11. Free article at Journal Website. PMID: 19054062

Symmons O, Váradi A, Arányi T. How segmental duplications shape our genome: recent evolution of ABCC6 and PKD1 Mendelian disease genes. Mol Biol Evol. 2008 Dec;25(12):2601-13. Free article at Journal Website. PMID: 18791038

Arányi T, Ratajewski M, Bardóczy V, Pulaski L, Bors A, Tordai A, Váradi A. Identification of a DNA methylation-dependent activator sequence in the pseudoxanthoma elasticum gene, ABCC6. J Biol Chem. 2005 May 13;280(19):18643-50. Free article at Journal Website. PMID: 15760889

Iliás A, Urbán Z, Seidl TL, Le Saux O, Sinkó E, Boyd CD, Sarkadi B, Váradi A. Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). J Biol Chem. 2002 May 10;277(19):16860-7. Free article at Journal Website. PMID: 11880368