Expression and in vivo rescue of human ABCC6 disease-causing mutants in mouse liver

Loss-of-function mutations in ABCC6 can cause chronic or acute forms of dystrophic mineralization described in disease models such as pseudoxanthoma elasticum (OMIM 26480) in human and dystrophic cardiac calcification in mice. The ABCC6 protein is a large membrane-embedded organic anion transporter...

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Veröffentlicht in:PloS one 2011-09, Vol.6 (9), p.e24738-e24738
Hauptverfasser: Le Saux, Olivier, Fülöp, Krisztina, Yamaguchi, Yukiko, Iliás, Attila, Szabó, Zalán, Brampton, Christopher N, Pomozi, Viola, Huszár, Krisztina, Arányi, Tamás, Váradi, András
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creator Le Saux, Olivier
Fülöp, Krisztina
Yamaguchi, Yukiko
Iliás, Attila
Szabó, Zalán
Brampton, Christopher N
Pomozi, Viola
Huszár, Krisztina
Arányi, Tamás
Váradi, András
description Loss-of-function mutations in ABCC6 can cause chronic or acute forms of dystrophic mineralization described in disease models such as pseudoxanthoma elasticum (OMIM 26480) in human and dystrophic cardiac calcification in mice. The ABCC6 protein is a large membrane-embedded organic anion transporter primarily found in the plasma membrane of hepatocytes. We have established a complex experimental strategy to determine the structural and functional consequences of disease-causing mutations in the human ABCC6. The major aim of our study was to identify mutants with preserved transport activity but failure in intracellular targeting. Five missense mutations were investigated: R1138Q, V1298F, R1314W, G1321S and R1339C. Using in vitro assays, we have identified two variants; R1138Q and R1314W that retained significant transport activity. All mutants were transiently expressed in vivo, in mouse liver via hydrodynamic tail vein injections. The inactive V1298F was the only mutant that showed normal cellular localization in liver hepatocytes while the other mutants showed mostly intracellular accumulation indicating abnormal trafficking. As both R1138Q and R1314W displayed endoplasmic reticulum localization, we tested whether 4-phenylbutyrate (4-PBA), a drug approved for clinical use, could restore their intracellular trafficking to the plasma membrane in MDCKII and mouse liver. The cellular localization of R1314W was significantly improved by 4-PBA treatment, thus potentially rescuing its physiological function. Our work demonstrates the feasibility of the in vivo rescue of cellular maturation of some ABCC6 mutants in physiological conditions very similar to the biology of the fully differentiated human liver and could have future human therapeutic application.
doi_str_mv 10.1371/journal.pone.0024738
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subjects Animal models
Animals
Biological Transport - genetics
Biological Transport - physiology
Biology
Calcification
Calcification (ectopic)
Cystic fibrosis
Deoxyribonucleic acid
Disease
DNA
Endoplasmic reticulum
Feasibility studies
Gene expression
Heart diseases
Hepatocytes
Humans
Intracellular
Liver
Liver - metabolism
Liver - pathology
Localization
Medicine
Membrane proteins
Membrane trafficking
Mice
Mice, Transgenic
Mineralization
Missense mutation
Molecular biology
Multidrug Resistance-Associated Proteins - genetics
Multidrug Resistance-Associated Proteins - metabolism
Mutants
Mutation
Phenylbutyric acid
Physiological aspects
Physiology
Proteins
Rodents
Structure-function relationships
Transport
Veins & arteries
title Expression and in vivo rescue of human ABCC6 disease-causing mutants in mouse liver
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