Mutation Altering the miR-184 Seed Region Causes Familial Keratoconus with Cataract Anne E. Hughes, Declan T. Bradley, Malcolm Campbell, Judith Lechner,

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Mutation Altering the miR-184 Seed Region Causes Familial Keratoconus with Cataract Anne E. Hughes, Declan T. Bradley, Malcolm Campbell, Judith Lechner, Durga P. Dash, David A. Simpson, Colin E. Willoughby The American Journal of Human Genetics Volume 89, Issue 5, Pages 628-633 (November 2011) DOI: 10.1016/j.ajhg.2011.09.014 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Massively Parallel Sequencing Reads Showing Point Mutation in MIR184 Multiple alignment of massively parallel sequence reads spanning the seed region of miR-184 from (A) a single individual affected with familial keratoconus and cataract, (B) a pool of seven affected members of the same family and (C) a pool of six unaffected members of the same family. All nucleotides that vary from the reference sequence, shown below, are indicated. Read depth and heterozygosity are designated at the top of each column. The American Journal of Human Genetics 2011 89, 628-633DOI: (10.1016/j.ajhg.2011.09.014) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Variants of miR-184 and Conservation across Species, Structure of miR-184, miR-205 and Mutant miR-184, and Interactions of miR-184 and miR-205 (A) Multiple alignment of miR-184 sequences from different vertebrate species. The mutation site (miR-184 r.57c>u, indicated by the blue arrow) is fully conserved across all species. Changes from the human reference sequence are shown in green type; the mature miRNAs are shown in red type, and the seed regions are in bold. The following abbreviations are used: hsa, Homo sapiens; ptr, Pan troglodytes; ppy, Pongo pygmaeus; mne, Macaca nemestrina; mdo, Monodelphis domestica; gga, Gallus gallus; ssc, Sus scrofa; rno, Rattus norvegicus; mmu, Mus musculus; xtr, Xenopus tropicalis; dre, Danio rerio. Fifty-four additional species showed full conservation of the mature miR-184 sequence. (B) Secondary structures and free energies of wild-type miR-184 and mutant miR-184 (r.57u) predicted by Mfold. (C) Target sites of miR-184 and miR-205 in the 3′ UTRs of INPPL1 and ITGB4 predicted by MicroCosm with energies shown in kcal/mol. The American Journal of Human Genetics 2011 89, 628-633DOI: (10.1016/j.ajhg.2011.09.014) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 Immunoblot of INPPL-1 and ITGB4 Knockdown by miRNAs was performed in HeLa cells. Signal strengths are shown for INPPL-1 and ITGB4 relative to a sham transfected control, all normalized for α-tubulin loading. One representative image is shown from five replicated experiments. (A) There was no rescue of miR-205 knockdown of INPPL-1 by the mutant miR-184 mimic compared to rescue of miR-205 knockdown of INPPL-1 by wild-type miR-184 mimic. (B) There was no rescue of miR-205 knockdown of ITGB4 by the mutant miR-184 mimic compared to rescue of miR-205 knockdown of ITGB4 by wild-type miR-184 mimic. The error bars represent 95% confidence interval for mean. The American Journal of Human Genetics 2011 89, 628-633DOI: (10.1016/j.ajhg.2011.09.014) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 4 Immunofluorescence Staining of INPPL-1, ITGB4, and Actin Representative micrographs showing (A and B) INPPL-1 (green) and actin (red) for cells transfected with (A) miR-184 mimic and miR-205 mimic and (B) mutant miR-184 and miR-205. The scale bar represents 50 μm. (C) Semiquantitative analysis of mutant miR-184 knockdown relative to wild-type miR-184, both in the presence of miR-205. All measurements were standardized for actin. The error bars represent 95% a confidence interval for mean. Representative micrographs showing (D and E) ITGB4 (green) and actin (red) for cells knocked down with (D) miR-184 mimic and miR-205 mimic and (E) mutant miR-184 and miR-205. The scale bar represents 50 μm. (F) Semiquantitative analysis of mutant miR-184 knockdown relative to wild-type miR-184, both with miR-205. All measurements were standardized for actin. The error bars represent 95% confidence interval for mean. The American Journal of Human Genetics 2011 89, 628-633DOI: (10.1016/j.ajhg.2011.09.014) Copyright © 2011 The American Society of Human Genetics Terms and Conditions