Analysis of Pseudoxanthoma Elasticum–Causing Missense Mutants of ABCC6 In Vivo; Pharmacological Correction of the Mislocalized Proteins Viola Pomozi,

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Analysis of Pseudoxanthoma Elasticum–Causing Missense Mutants of ABCC6 In Vivo; Pharmacological Correction of the Mislocalized Proteins Viola Pomozi, Christopher Brampton, Krisztina Fülöp, Li-Hsieh Chen, Ailea Apana, Qiaoli Li, Jouni Uitto, Olivier Le Saux, András Váradi Journal of Investigative Dermatology Volume 134, Issue 4, Pages 946-953 (April 2014) DOI: 10.1038/jid.2013.482 Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Positions of the investigated mutants in the membrane topology model of ABCC6 protein and their transport activity. (a) The model is based on our earlier publication (Tusnády et al., 2006); the positions of the various domains are indicated by horizontal arrows. Conserved sequence motifs, ABC signatures, Q-loops, and Walker B motifs are colored, and the positions of known disease-causing missense mutations are indicated with red color. Arrows point to the positions of mutants investigated in the present study. (b) Protein variants were expressed in Sf9 insect cell system, and their ATP-dependent transport activity was assayed in the presence of 50 nM [3H]LTC4 as substrate. Transport activity was compared with that of the wild-type (wt) protein (100%). Each assay has been performed on two independent membrane preparations in triplicate. LTC, leukotriene C4. Journal of Investigative Dermatology 2014 134, 946-953DOI: (10.1038/jid.2013.482) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Subcellular localization of ABCC6 variants expressed in MDCKII (Madin–Darby canine kidney) cells and the effect of 4-phenylbutyrate (4-PBA) treatment on their localization. ABCC6 was detected by immunofluorescence using mAb M6-II7 (green color); anti-Na,K-ATPase pAb was used to detect Na,K-ATPase as a plasma membrane localization marker (red color). Cells overexpressing ABCC6 variants were grown with or without 1 mM 4-PBA either on plastic (nonpolarized) or on Transwell membrane (polarized). Confocal laser microscopy images were collected together with Z-stack images in the case of polarized cell cultures. Bar=20 μm. Journal of Investigative Dermatology 2014 134, 946-953DOI: (10.1038/jid.2013.482) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Subcellular localization of ABCC6 variants expressed in mouse liver and the effect of 4-phenylbutyrate (4-PBA) treatment on their localization. The human and mouse ABCC6/Abcc6 were detected on frozen sections by immunofluorescence using mAb M6-II7 (green color) and the S-20 polyclonal antibody (red), respectively. Mice received three intraperitoneal injections of 4-PBA (100 mg/kg-1 per day) before performing hydrodynamic tail-vein injections and received 6.25 mg ml-1 4-PBA in drinking water during the entire experiment. Journal of Investigative Dermatology 2014 134, 946-953DOI: (10.1038/jid.2013.482) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Rescue of the morpholino-induced phenotype by human ABCC6 mRNA in zebrafish embryos. Human ABCC6 cDNA variants were cloned into Bluescript II SK+ vector, mRNA was generated by in vitro transcription, and 2–4 ng of mRNA was injected into ∼100 embryos together with 12–18 ng of MO1 morpholino (MO1; for sequence, see Li et al., 2010). Animals were photographed 3 days after injection. (a) Control animals injected with standard control morpholino. (b) Animals injected with morpholino. (c) Animals injected with morpholino and with wtABCC6 mRNA. (d) Animals injected with morpholino and with ABCC6 R1141X mRNA. wt, wild type. Journal of Investigative Dermatology 2014 134, 946-953DOI: (10.1038/jid.2013.482) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions