Functional Rescue of ABCC6 Deficiency by 4-Phenylbutyrate Therapy Reduces Dystrophic Calcification in Abcc6-/-Mice.
Soft-tissue calcification is associated with aging, common conditions such as diabetes or hypercholesterolemia, and with certain genetic disorders. ABCC6 is an efflux transporter primarily expressed in liver facilitating the release of adenosine triphosphate from hepatocytes. Within the liver vasculature, adenosine triphosphate is converted into pyrophosphate, a major inhibitor of ectopic calcification. ABCC6 mutations thus lead to reduced plasma pyrophosphate levels, resulting in the calcification disorder pseudoxanthoma elasticum and some cases of generalized arterial calcification of infancy. Most mutations in ABCC6 are missense, and many preserve transport activity but are retained intracellularly. We have previously shown that the chemical chaperone 4-phenylbutyrate (4-PBA) promotes the maturation of ABCC6 mutants to the plasma membrane. In a humanized mouse model of pseudoxanthoma elasticum, we investigated whether 4-PBA treatments could rescue the calcification inhibition potential of selected ABCC6 mutants. We used the dystrophic cardiac calcification phenotype of Abcc6-/-mice as an indicator of ABCC6 function to quantify the effect of 4-PBA on human ABCC6 mutants transiently expressed in the liver. We showed that 4-PBA administrations restored the physiological function of ABCC6 mutants, resulting in enhanced calcification inhibition. This study identifies 4-PBA treatment as a promising strategy for allele-specific therapy of ABCC6-associated calcification disorders.
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA; Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary.
Viola
V
Pomozi
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
Christopher
C
Brampton
Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary.
Flóra
F
Szeri
Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary.
Dóra
D
Dedinszki
Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary.
Eszter
E
Kozák
Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Koen
K
van de Wetering
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
Hi'ilani
H
Hopkins
University of Angers, Angers, France; CHU Angers, Centre de consultation PXE, Angers, France.
Ludovic
L
Martin
Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary.
András
A
Váradi
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA. Electronic address: Lesaux@hawaii.edu.
Olivier
O
Le Saux
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology; D000483:Alleles; D000818:Animals; D002114:Calcinosis / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000502:physiology*; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D010654:Phenylbutyrates / Q000627:therapeutic use*; D011561:Pseudoxanthoma Elasticum / Q000188:drug therapy* / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010654:Phenylbutyrates; C102029:ABCC6 protein, human; C504743:Abcc6 protein, mouse; C075773:4-phenylbutyric acid