Functional Rescue of ABCC6 Deficiency by 4-Phenylbutyrate Therapy Reduces Dystrophic Calcification in Abcc6–/– Mice

Viola Pomozi, Christopher Brampton, Flóra Szeri, Dóra Dedinszki, Eszter Kozák, Koen van de Wetering, Hi'ilani Hopkins, Ludovic Martin, A. Váradi, Olivier Le Saux

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)595-602
Number of pages8
JournalJournal of Investigative Dermatology
Volume137
Issue number3
DOIs
Publication statusPublished - Mar 1 2017

Fingerprint

Pseudoxanthoma Elasticum
Liver
Rubber
Adenosine Triphosphate
Therapeutics
Mutation
Inborn Genetic Diseases
Cell membranes
Medical problems
Hypercholesterolemia
Hepatocytes
Aging of materials
Alleles
Cell Membrane
4-phenylbutyric acid
Tissue
Phenotype
Plasmas
diphosphoric acid
Arterial calcification of infancy

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Functional Rescue of ABCC6 Deficiency by 4-Phenylbutyrate Therapy Reduces Dystrophic Calcification in Abcc6–/– Mice. / Pomozi, Viola; Brampton, Christopher; Szeri, Flóra; Dedinszki, Dóra; Kozák, Eszter; van de Wetering, Koen; Hopkins, Hi'ilani; Martin, Ludovic; Váradi, A.; Le Saux, Olivier.

In: Journal of Investigative Dermatology, Vol. 137, No. 3, 01.03.2017, p. 595-602.

Research output: Contribution to journalArticle

Pomozi, V, Brampton, C, Szeri, F, Dedinszki, D, Kozák, E, van de Wetering, K, Hopkins, H, Martin, L, Váradi, A & Le Saux, O 2017, 'Functional Rescue of ABCC6 Deficiency by 4-Phenylbutyrate Therapy Reduces Dystrophic Calcification in Abcc6–/– Mice', Journal of Investigative Dermatology, vol. 137, no. 3, pp. 595-602. https://doi.org/10.1016/j.jid.2016.10.035
Pomozi, Viola ; Brampton, Christopher ; Szeri, Flóra ; Dedinszki, Dóra ; Kozák, Eszter ; van de Wetering, Koen ; Hopkins, Hi'ilani ; Martin, Ludovic ; Váradi, A. ; Le Saux, Olivier. / Functional Rescue of ABCC6 Deficiency by 4-Phenylbutyrate Therapy Reduces Dystrophic Calcification in Abcc6–/– Mice. In: Journal of Investigative Dermatology. 2017 ; Vol. 137, No. 3. pp. 595-602.
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