Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin Peter.

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Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin Peter Huppke, Cornelia Brendel, Vera Kalscheuer, Georg Christoph Korenke, Iris Marquardt, Peter Freisinger, John Christodoulou, Merle Hillebrand, Gaele Pitelet, Callum Wilson, Ursula Gruber-Sedlmayr, Reinhard Ullmann, Stefan Haas, Orly Elpeleg, Gudrun Nürnberg, Peter Nürnberg, Shzeena Dad, Lisbeth Birk Møller, Stephen G. Kaler, Jutta Gärtner The American Journal of Human Genetics Volume 90, Issue 1, Pages 61-68 (January 2012) DOI: 10.1016/j.ajhg.2011.11.030 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Family Pedigrees (A) Patients 1 and 2; (B) patient 3; (C) patient 4; (D) patient 5. The American Journal of Human Genetics 2012 90, 61-68DOI: (10.1016/j.ajhg.2011.11.030) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Cranial MRI Images Patient 3 at age 36 months (A, B) and patient 5 at age 14 months (C, D). Sagittal T1 images (A, C) demonstrate cerebellar hypoplasia (white arrows); transversal T2 images (B, D) show wide subarachnoid spaces (black arrows) and hypomyelination (∗). The American Journal of Human Genetics 2012 90, 61-68DOI: (10.1016/j.ajhg.2011.11.030) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Genomic Structure and Localization of the Mutations in the SLC33A1 Gene The coding region is depicted in gray. Missense mutation, arrow; nonsense mutation, X; splice site mutation, asterisk; insertion, down triangle; deletion, up triangle. The American Journal of Human Genetics 2012 90, 61-68DOI: (10.1016/j.ajhg.2011.11.030) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 Consequences of the Mutations (A) Quantitative real-time PCR analyses revealing unchanged (P4 = patient 4) and significantly reduced (P3 = patient 3 and P5 = patient 5) SLC33A1 expression in patient fibroblasts compared to a normal control cell line. Statistical analysis was done by an unpaired Student's t test compared to wild-type expression in control cells. Errors are given as SEM. The p values (∗p < 0.0001; ∗∗p = 0.0040) were adjusted according to Bonferroni. (B) Western blot analysis of cell extracts (30 μg) from transiently transfected MCF-7 cells expressing the wild-type and mutated forms of AT-1. The blot was probed with a mouse monoclonal FLAG antibody. Untransfected cells and the housekeeping gene GAPDH were used as controls. (C) Subcellular localization of wild-type and mutated AT-1. The proteins were visualized by indirect immunofluorescent analysis of MCF-7 cells transiently transfected with different FLAG-AT-1 expression constructs (red). The cells were fixed, permeabilized, and incubated with the monoclonal antibody raised against the FLAG epitope. The wild-type AT-1 protein shows a perinuclear cytoplasmic localization, where it colocalizes with the Golgi marker proteins Giantin and Syntaxin 6 (green, 1.A–1.C and 2.A–2.C). The protein carrying the missense mutation Ala110Pro produced a punctate pattern and localized neither with the Golgi nor with the ER (PDI, 1.D–1.F, 2.D–2.F, 3.D–3.F). The 184-amino-acid-long truncated AT-1 protein mimicking the nonsense mutation Tyr366∗ was found in the cytoplasm, where the staining pattern coincided with the ER marker PDI (3.G–3.I). The nuclei were counterstained with DAPI and scale bars represent 10 μm. The American Journal of Human Genetics 2012 90, 61-68DOI: (10.1016/j.ajhg.2011.11.030) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 5 Downregulation of AT-1 Reduces Ceruloplasmin Secretion in HepG2 Cells (A) Quantitative real-time PCR analysis revealing unchanged (ns siRNA) and statistically significant reduced (siRNA) SLC33A1 expression in HepG2 cells 2 days after transfection with and without siRNA (control). (B) Densitometric quantification of three independent western blot experiments. 30 μl medium of the equal number of HepG2 cells were analyzed 2 days after transfection with SLC33A1-specific siRNA (control). Compared to cells transfected without siRNA (control) or nonsilencing siRNA (ns siRNA) Ceruloplasmin (black bars), secretion was ∼30% reduced but albumin (gray bars) secretion unaltered in cells transfected with SLC33A1-specific siRNA (siRNA). Statistical analysis was done by an unpaired Student's t test compared to wild-type expression in control cells. Errors are given as SEM. The p values were adjusted according to Bonferroni (∗∗p < 0.0001, ∗∗∗p = 0.0001). The American Journal of Human Genetics 2012 90, 61-68DOI: (10.1016/j.ajhg.2011.11.030) Copyright © 2012 The American Society of Human Genetics Terms and Conditions