Alice E. Davidson, Ian D. Millar, Jill E

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Date of download: 5/30/2016 Copyright © 2016 American Medical Association. All rights reserved. From: An Unusual Retinal Phenotype Associated With a Novel.

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Missense Mutations in a Retinal Pigment Epithelium Protein, Bestrophin-1, Cause Retinitis Pigmentosa Alice E. Davidson, Ian D. Millar, Jill E. Urquhart, Rosemary Burgess-Mullan, Yusrah Shweikh, Neil Parry, James O'Sullivan, Geoffrey J. Maher, Martin McKibbin, Susan M. Downes, Andrew J. Lotery, Samuel G. Jacobson, Peter D. Brown, Graeme C.M. Black, Forbes D.C. Manson The American Journal of Human Genetics Volume 85, Issue 5, Pages 581-592 (November 2009) DOI: 10.1016/j.ajhg.2009.09.015 Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of Families (A) Family 1 had a history of adRP. The proband is IV-13. (B) Family 5. The proband (III-5) was diagnosed with adRP, but sequencing revealed that all tested affected family members were homozygous for p.L140V. This suggests that the proband's mother is heterozygous for the same mutation. Neither the proband's mother nor any of her unaffected siblings have reported or been diagnosed with symptoms of RP, suggesting that in this family RP is recessively inherited. All ten coding exons and the flanking intronic sequences of BEST1 were sequenced in the probands from each family. Family members indicated with ⋄ were sequenced for the respective exon that was mutated in the family proband (exon 5 in family 1 and exon 6 in family 5). The American Journal of Human Genetics 2009 85, 581-592DOI: (10.1016/j.ajhg.2009.09.015) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 2 Retinal Images (A and B) Family 1. Fundus images of left eyes of individual IV-15 (A), showing mid peripheral flecks (white arrows) and pigment clumping (black arrows), and of IV-1 (B), demonstrating severe vascular attenuation (arrows) and disc pallor (circled). (C and D) Family 2. Fundus images of affected siblings, showing the dense pigmentary changes (black areas) that were present in all quadrants of the peripheral retina and the abrupt change to a more-normal-appearing central retina (arrows). Inferotemporal left retina of the female proband (P1) at age 30 years (C) and inferior left retina of the proband's brother (P2) at age 40 years (D). (E and F) Family 3. Color fundus photos of the posterior pole (top) and inferior retina (bottom) of the right and left eyes of the proband in family 3 (F), with normal autofluorescence imaging of the posterior poles (E). Bone spiculation is seen in the peripheral retina only (arrows in F). (G and H) Family 4. Fundus images of the left (G) and right (H) eyes of the proband. Note the abrupt demarcation between normal (light areas) and abnormal (dark areas) peripheral retina. RPE degeneration and bone-spicule-like pigment clumping (arrows) were present circumferentially in both eyes. (I–K) Family 5. Proband (III-5), 23 years of age, showing total serous retinal detachment in the right eye (arrows), with central yellow deposit (I) and retinal detachment extending nasally (J). Autofluorescence imaging in individual III-2, showing increased signal in area of yellow deposits (arrows) (K). The American Journal of Human Genetics 2009 85, 581-592DOI: (10.1016/j.ajhg.2009.09.015) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 3 Multiple Alignment of Bestrophin-1 around the Residues Mutated in RP The amino acid sequence of bestrophin-1 incorporating the four RP mutations (p.L140V, p.I205T, p.Y227C, p.D228N; shaded boxes) is shown for ten orthologs (Homo sapiens, Pan troglodytes, Macaca mulatta, Bos taurus, Canis familiaris, Mus musculus, Rattus norvegicus, Gallus gallus, Xenopus tropicalis, Danio rerio) The alignment was performed with ClustalW, and the sequence accession numbers are those quoted in Milenkovic et al.49 The American Journal of Human Genetics 2009 85, 581-592DOI: (10.1016/j.ajhg.2009.09.015) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 4 Cl− Channel Activity Associated with the Expression of p.I205T and p.L140V in HEK293 Cells (A–C)Whole-cell current records in cells transfected with (A) eGFP, (B) WT bestrophin-1, and (C) p.I205T. Currents were evoked with 450 ms voltage steps (Vm) from −120 mV to 80 mV in increments of 20 mV. The holding Vm was −50 mV. (D) Current density is plotted as a function of Vm for cells transfected with WT bestrophin-1 (■; n = 10), p.I205T (♦; n = 10), and WT plus p.I205T (∇; n = 7). (E) Outward conductances measured for combinations of WT and mutant bestrophins. Conductances were measured between Vm = 60–80 mV, and the values were normalized to the mean WT conductance for each series of experiments. In the p.L140V series of experiments, the number of patched cells were as follows: WT, n = 14; p.I205T, n = 12; and WT plus p.I205T, n = 14. Results are presented as mean ± standard error of the mean. An asterisk denotes a significant difference (p < 0.05). The American Journal of Human Genetics 2009 85, 581-592DOI: (10.1016/j.ajhg.2009.09.015) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 5 Cellular Localization of Bestrophin-1 Isoforms in MDCK II and HEK293 Cells Transiently transfected MDCK II cells (A–D and F) were polarized on Transwell membranes before immunofluorescent labeling with bestrophin-1 antibody (green in A–D and F) and confocal microscopy. Nuclei were labeled with DAPI (blue). A representative lateral (Z-stack) image is shown. WT (A) and p.I205T (B) isoforms localized to the basolateral membrane. A vertical optical section shows that WT bestrophin-1 (green) localizes basal to the tight junction maker ZO-1 (red) (insert, A). The p.L140V (C) and p.D228N (D) isoforms exhibited a diffuse cytoplasmic localization. The p.D312N mutant isoform has a cytoplasmic localization (E). WT bestrophin-1 (red) expressed in HEK-293 cells does not traffic to the cell membrane (F). The American Journal of Human Genetics 2009 85, 581-592DOI: (10.1016/j.ajhg.2009.09.015) Copyright © 2009 The American Society of Human Genetics Terms and Conditions