Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa

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Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa Gavin Arno, Smriti A. Agrawal, Aiden Eblimit, James Bellingham, Mingchu Xu, Feng Wang, Christina Chakarova, David A. Parfitt, Amelia Lane, Thomas Burgoyne, Sarah Hull, Keren J. Carss, Alessia Fiorentino, Matthew J. Hayes, Peter M. Munro, Ralph Nicols, Nikolas Pontikos, Graham E. Holder Graeme Black, Georgina Hall, Stuart Ingram, Rachel Gillespie, Forbes Manson, Panagiotis Sergouniotis, Chris Inglehearn, Carmel Toomes, Manir Ali, Martin McKibbin, James Poulter, Kamron Khan, Emma Lord, Andrea Nemeth, Susan Downes, Jing Yu, Stefano Lise, Gavin Arno, Alessia Fiorentino, Nikos Ponitkos, Vincent Plagnol, Michel Michaelides, Alison J. Hardcastle, Michael E. Cheetham, Andrew R. Webster, Veronica van Heyningen, Chinwe Asomugha, F. Lucy Raymond, Anthony T. Moore, Vincent Plagnol, Michel Michaelides, Alison J. Hardcastle, Yumei Li, Catherine Cukras, Andrew R. Webster, Michael E. Cheetham, Rui Chen Gavin Arno, Smriti A. Agrawal, Aiden Eblimit, James Bellingham, Mingchu Xu, Feng Wang, Christina Chakarova, David A. Parfitt, Amelia Lane, Thomas Burgoyne, Sarah Hull, Keren J. Carss, Alessia Fiorentino, Matthew J. Hayes, Peter M. Munro, Ralph Nicols, Nikolas Pontikos, Graham E. Holder Graeme Black, Georgina Hall, Stuart Ingram, Rachel Gillespie, Forbes Manson, Panagiotis Sergouniotis, Chris Inglehearn, Carmel Toomes, Manir Ali, Martin McKibbin, James Poulter, Kamron Khan, Emma Lord, Andrea Nemeth, Susan Downes, Jing Yu, Stefano Lise, Gavin Arno, Alessia Fiorentino, Nikos Ponitkos, Vincent Plagnol, Michel Michaelides, Alison J. Hardcastle, Michael E. Cheetham, Andrew R. Webster, Veronica van Heyningen, Chinwe Asomugha, F. Lucy Raymond, Anthony T. Moore, Vincent Plagnol, Michel Michaelides, Alison J. Hardcastle, Yumei Li, Catherine Cukras, Andrew R. Webster, Michael E. Cheetham, Rui Chen The American Journal of Human Genetics Volume 99, Issue 6, Pages 1305-1315 (December 2016) DOI: 10.1016/j.ajhg.2016.10.008 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Autosomal-Recessive RP Families and Associated REEP6 Variants (A) Pedigrees of all families with RP in this study (families A to E). Proband II.1 from family A is compound heterozygous for REEP6 variants (M1/M2). All other affected individuals were homozygous for the respective REEP6 variants indicated (M3, M4, M5, M6). M3 c.−5835_115+936delinsAC027307.5:79083_79240inv is abbreviated to c.−5835_115+936delins. (B) REEP6 gene structure with nucleotide positions for M1 to M6 mapped on to exons (E1–E6). Exon 5 is present only in isoform REEP6.1 (absent from REEP6.2). Protein structure of REEP6.1 and REEP6.2 with position of the corresponding mutations indicated. (C) Sequence reads from individual A-II:1 aligned against + strand of hg19 showing heterozygous mutations in REEP6. Both mutations are in exon 4: c.T404C (p.Ala150Profs∗2) and c.448delG (p.Leu135Pro) are in trans. The American Journal of Human Genetics 2016 99, 1305-1315DOI: (10.1016/j.ajhg.2016.10.008) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Clinical Findings for Individuals with Autosomal-Recessive RP Harboring REEP6 Variants (A) Retinal imaging of the left eye of individual II:1 at age 18 years from family A. (B) Retinal imaging of the left eye of individual II:8 at age 32 years from family B. (C) Right eye retinal imaging of individual II:5 at age 54 years from family D. (D) Retinal imaging of the right eye of individual II:4 from family E. Fundus imaging, fundus autofluorescence imaging, and optical coherence tomography (OCT) scan reveal typical retinitis pigmentosa features in all affected individuals. Color fundus photographs demonstrate severely constricted retinal arterioles, mid-peripheral retinal pigment epithelium (RPE) atrophy, retinal atrophy within and extending outward of vascular arcades, and intraretinal pigmented spicules. Fundus autofluorescence imaging demonstrates a hyperautofluorescent ring around fovea and areas of circumscribed hypoautofluorescence within and extending outward of vascular arcades. OCT demonstrates atrophy of the outer retina with small bands of retained photoreceptors (arrows) that correspond to the areas within the para-foveal rings. The American Journal of Human Genetics 2016 99, 1305-1315DOI: (10.1016/j.ajhg.2016.10.008) Copyright © 2016 The Authors Terms and Conditions

Figure 3 Expression and Localization of REEP6 in Human iPSC Photoreceptors (A) Reverse-transcription PCR analysis of REEP6.1 and 6.2 isoforms in control adult fibroblasts (fibs) and control BJ optic cups during different weeks (wk) of photoreceptor differentiation. GAPDH used a loading control. (B) Maturing rhodopsin-positive rod cells (green) co-express REEP6 (red) in the IS and cell body (CB). At a later stage of development, mature rods develop rhodopsin-laden outer segments (green) in which REEP6 staining (red) is not detectable despite its continued expression in the IS and CB. (C) REEP6 (red) is not detectable in maturing cones, expressing cone arrestin (green). Mature cones (green) remain REEP6 (red) negative at this stage of development. Nuclei are counter-stained with DAPI (blue). (D) ER localization of REEP6.1. REEP6.1 WT (green) was expressed in SK-N-SH cells, stained with anti-REEP6, and counterstained with anti-KDEL (red). Scale bars represent 10 μm. The American Journal of Human Genetics 2016 99, 1305-1315DOI: (10.1016/j.ajhg.2016.10.008) Copyright © 2016 The Authors Terms and Conditions

Figure 4 Reep6L135P/L135P Mutant Mice Exhibit Photoreceptor Degeneration (A) Histological analysis of retinal sections from Reep6+/L135P (left) and Reep6L135P/L135P (right) mice was performed at 4 months and 6 months of age. Reep6+/L135P retina shows normal layered organization compared to the Reep6L135P/L135P retina that shows moderate thinning of the outer nuclear layer (ONL) at 4 months and marked thinning at 6 months of age. “INL” indicates inner nuclear layer. Scale bars represent 40 μm. (B) TEM images of P20 and 6-month-old retina from Reep6+/L135P control retina and Reep6L135P/L135P mutant retina shows thinning of ONL, outer segment (OS), and inner segment (IS) at 6 months of age indicative of progressive retinal degeneration. Scale bars represent 2 μm (top) and 10 μm (bottom). (C) Quantitative evaluation of scotopic a-wave and b-wave and photopic b-wave amplitude data for 4-month-old Reep6+/L135P control retina and Reep6L135P/L135P mutant mice. NS indicates not significant, ∗∗significant at p < 0.01, ∗∗∗significant at p < 0.001. The American Journal of Human Genetics 2016 99, 1305-1315DOI: (10.1016/j.ajhg.2016.10.008) Copyright © 2016 The Authors Terms and Conditions