S. Amer Riazuddin, Amber Shahzadi, Christina Zeitz, Zubair M

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A Mutation in SLC24A1 Implicated in Autosomal-Recessive Congenital Stationary Night Blindness S. Amer Riazuddin, Amber Shahzadi, Christina Zeitz, Zubair M. Ahmed, Radha Ayyagari, Venkata R.M. Chavali, Virgilio G. Ponferrada, Isabelle Audo, Christelle Michiels, Marie-Elise Lancelot, Idrees A. Nasir, Ahmad U. Zafar, Shaheen N. Khan, Tayyab Husnain, Xiaodong Jiao, Ian M. MacDonald, Sheikh Riazuddin, Paul A. Sieving, Nicholas Katsanis, J. Fielding Hejtmancik The American Journal of Human Genetics Volume 87, Issue 4, Pages 523-531 (October 2010) DOI: 10.1016/j.ajhg.2010.08.013 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of Family PKRP070 with Alleles for Chromosome 15q Markers Alleles forming the risk haplotypes are shaded black, alleles cosegregating with the risk haplotype without homozygosity are shaded gray, and alleles not cosegregating with CSNB are shown in white. The American Journal of Human Genetics 2010 87, 523-531DOI: (10.1016/j.ajhg.2010.08.013) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Fundus Photographs of Family PKRP070 (A) OD and OS of affected individual 14. (B) OD and OS of affected individual 18. (C) OD and OS of affected individual 28. (D) OD and OS of affected individual 34. (E) OD and OS of unaffected individual 35. OD, oculus dexter (right eye); OS, oculus sinister (left eye). The American Journal of Human Genetics 2010 87, 523-531DOI: (10.1016/j.ajhg.2010.08.013) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 Sequence Chromatogram Illustrating the Causal Lesions and the Topological Model of SLC24A1 (A–C) Individual 11 (A), individual 12 (B), and individual 14 (C) show the wild-type allele, heterozygous, and homozygous 2 bp deletion c.1613_1614del, respectively. The underlined are the two bases deleted in the affected individuals of family PKFP070. (D) Transmembrane domains of SLC24A1 predicted by Simple Modular Architecture Research Tools (SMART) algorithms. The deletion mutation resides in the fourth transmembrane that constitutes the first of two proposed ion exchanger domains of SLC24A1. The American Journal of Human Genetics 2010 87, 523-531DOI: (10.1016/j.ajhg.2010.08.013) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 4 Quantitative Expression Analyses in the Adult Mouse Eye Tissue (A) Expression of Slc24a1 and Rhodopsin was determined by qRT-PCR in the mouse eyes at P01, P03, P05, P10, P15, and P30. Slc24a1 expression is presented as bars on an arbitrary scale, and Rhodopsin expression is presented as a line. All values are the mean (± SEM) of three independent observations after normalization with the control gene (Rpl-19) expression. (B) Quantitative expression of Slc24a1 in adult mouse eye tissue (180 days). Slc24a1 expression is presented as bars using an arbitrary scale on the y axis. Values are presented as the mean (± SEM) of three independent observations after normalization with the control gene (Rpl-19) expression. RPE, retinal pigment epithelium; ON, optic nerve. The American Journal of Human Genetics 2010 87, 523-531DOI: (10.1016/j.ajhg.2010.08.013) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 5 Localization of SLC24A1 in Human Retina with In Situ Hybridization Using Digoxigenin-Labeled Sense and Antisense Probes Hybridization with sense probe as a control (left) and antisense probe (right) show strong labeling (black arrows) in the inner segment, outer and inner nuclear layers, and ganglion cell layer. OS, outer segment; IS, inner segment; ONL, outer nuclear layer; OPL, outer plexiform layer; IPL, inner plexiform layer; GCL, ganglion cell layer. The American Journal of Human Genetics 2010 87, 523-531DOI: (10.1016/j.ajhg.2010.08.013) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 6 Immunolocalization of Slc24a1 Expression in P13 and Adult Mouse Retinal Layers The slides were stained for Slc24a1 with goat anti-rabbit IgG conjugated with AlexaFluor 594 (red), F-actin using AlexaFluor488 conjugated phalloidin (green), and nuclei using Hoechst 33342 (blue). Merge represents an overlay of images from the first three columns in P13 and adult mouse retinal layers, respectively. The localization pattern illustrates a strong signal in the inner segment, outer and inner nuclear layers, and ganglion cell layer. The scale bar represents 50 um. OS, outer segment; IS, inner segment; ONL, outer nuclear layer; OPL, outer plexiform layer; IPL, inner plexiform layer; GCL, ganglion cell layer. The American Journal of Human Genetics 2010 87, 523-531DOI: (10.1016/j.ajhg.2010.08.013) Copyright © 2010 The American Society of Human Genetics Terms and Conditions