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TULP1 Mutations Causing Early-Onset Retinal Degeneration: Preserved but Insensitive Macular Cones

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Retina TULP1 Mutations Causing Early-Onset Retinal Degeneration: Preserved but Insensitive Macular Cones Samuel G. Jacobson,1 Artur V. Cideciyan,1 Wei Chieh Huang,1 Alexander Sumaroka,1 Alejandro J. Roman,1 Sharon B. Schwartz,1 Xunda Luo,1 Rebecca Sheplock,1 Joanna M. Dauber,1 Malgorzata Swider,1 and Edwin M. Stone2,3 1Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States 2Department of Ophthalmology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States 3Howard Hughes Medical Institute, Iowa City, Iowa, United States Correspondence: Samuel G. Jacob- PURPOSE. To investigate visual function and outer and inner retinal structure in the rare form of son, Scheie Eye Institute, University retinal degeneration (RD) caused by TULP1 (tubby-like protein 1) mutations. of Pennsylvania, 51 N. 39th Street, Philadelphia, PA 19104, USA; METHODS. Retinal degeneration patients with TULP1 mutations (n ¼ 5; age range, 5–36 years) [email protected]. were studied by kinetic and chromatic static perimetry, en face autofluorescence imaging, and spectral-domain optical coherence tomography (OCT) scans. Outer and inner retinal Submitted: April 10, 2014 Accepted: July 13, 2014 laminar thickness were measured and mapped across the central retina. Comparisons were made with results from patients with RD associated with four ciliopathy genotypes (MAK, Citation: Jacobson SG, Cideciyan AV, RPGR, BBS1, and USH2A). Huang WC, et al. TULP1 mutations causing early-onset retinal degenera- RESULTS. The TULP1-RD patients were severely affected already in the first decade of life and tion: preserved but insensitive macu- there was rapidly progressive visual loss. No evidence of rod function was present at any age. lar cones. Invest Ophthalmol Vis Sci. Small central islands showed melanized retinal pigment epithelium by autofluorescence 2014;55:5354–5364. DOI:10.1167/ imaging and well-preserved photoreceptor laminar thickness by OCT imaging. There was iovs.14-14570 extracentral loss of laminar architecture and increased inner retinal thickening. Structure- function relationships in residual foveal cone islands were made in TULP1-RD patients and in other retinopathies considered ciliopathies. Patients with TULP1-RD, unlike the others, had greater dysfunction for the degree of foveal structural preservation. CONCLUSIONS. Retinal degeneration with TULP1 mutations leads to a small central island of residual foveal cones at early ages. These cones are less sensitive than expected from the residual structure. The human phenotype is consistent with experimental evidence in the Tulp1 knockout mouse model that visual dysfunction could be complicated by abnormal processes proximal to cone outer segments. Keywords: cilia, optical coherence tomography, Leber congenital amaurosis, rod, cone he discovery of the tubby gene family1 and disease photoreceptors remaining in the retinas of molecularly T association of the gene encoding tubby-like protein 1 clarified patients.21,22 Photoreceptor laminar integrity as (TULP1) with retinitis pigmentosa (RP) 14, an autosomal measured by optical coherence tomography (OCT) can recessive (ar) retinal degeneration locus on chromosome 6p, provide the information suggesting which of the therapeutic occurred more than a decade ago.2–6 This was followed by directions would be most appropriate to consider and develop reports of patients with TULP1 mutations and clinical in the future for patients with TULP1-associated RD. We descriptions that continued to describe the disease as arRP or studied a cohort of patients with TULP1 mutations and used alternative diagnoses such as early-onset retinal degener- determined retinal laminar architecture as well as visual 7–15 ation (EORD) or Leber congenital amaurosis (LCA). function to provide information about treatment potential for What do we know about retinal disease mechanisms in this disease. The wider question posed was whether the À/À TULP1 deficiency? The tulp1 knockout mouse (tulp1 ) shows pattern of phenotype results in patients with TULP1 progressive loss of rod and cone photoreceptor nuclei over the mutations was different from those of other retinal degener- first 4 to 5 months of life. Tulp1 is located in the photoreceptor ations considered ciliopathies.23–25 inner segments of wild-type mice. Accumulation of vesicles in the interphotoreceptor matrix was noted in tulp1À/À mice and attributed to transport abnormalities from inner segment to METHODS outer segment.16–18 It has also been suggested that Tulp1 is 19 critical for development of the photoreceptor synapse and Subjects may have a role in phagocytosis.20 Any ongoing or planned therapeutic directions for forms of There were five RD patients, representing four families, with EORD or LCA depend on whether there are detectable TULP1 mutations and 32 patients with other molecularly Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. www.iovs.org j ISSN: 1552-5783 5354 Downloaded from tvst.arvojournals.org on 09/26/2021 TULP1 and Other Ciliopathies IOVS j August 2014 j Vol. 55 j No. 8 j 5355 TABLE. Clinical and Molecular Characteristics of the Patients Visual Acuity† Refraction‡ Age at Previous Patient Visits, y Sex Allele 1/Allele 2 RE LE RE LE Report§ TULP1jj P1¶ 4,10,15 F p.Q301Ter/p.Q301Ter 20/160 20/125 À1.25 À1.25 P2¶ 9,15,19 M p.Q301Ter/p.Q301Ter 20/200 20/200 þ6.00 þ6.00 P3 17,25 F p.G368W/p.D355V 20/80 20/80 Plano þ0.50 P4 27,36 M p.R400Q/p.Y321D HM HM À1.25 À1.50 P5 28,33 F p.R400W/p.R400W 20/100 20/100 þ5.75 þ6.75 MAK# P6 55 M p.K429 insAlu_353bp/p.K429 insAlu_353bp 20/20 20/25 À1.50 À2.50 P7** 59 F p.K429 insAlu_353bp/p.K429 insAlu_353bp 20/40 20/63 À7.00 À8.00 P654 P8** 72 F p.K429 insAlu_353bp/p.K429 insAlu_353bp 20/25 20/20 Plano Plano P954 RPGR‡‡ P9 7 M p.S551fs 20/30 20/30 À0.75 À0.75 P10 15 M p.E746fs 20/25 20/20 À3.25 À3.75 P16, F576 P11 17 M p.E802fs 20/50 20/32 þ1.75 þ2.75 P12 22 M p.E746fs 20/40 20/25 À2.00 À2.50 P29, F1576 P13 25 M p.G743Ter 20/50 20/30 þ0.75 þ0.75 P19, F776 P14 27 M p.E872Ter 20/32 20/40 À4.50 À5.25 P20, F876 P15 28 M p.E915Ter 20/25 20/25 À3.25 À4.25 P30, F1676 P16 38 M p.G702fs 20/63 20/50 À1.50 À1.50 P18, F676 P17 42 M p.E802fs 20/32 20/32 À5.25 À4.00 P5, F176 P18 45 M p.E802fs 20/100 20/40 À4.25 À3.00 P19 45 M p.L460fs 20/32 20/25 þ2.25 þ1.75 P20 46 M p.E956fs 20/160 20/160 À0.75 À0.50 P21 47 M p.E839fs 20/300 20/150 À2.00 À2.00 P22 51 M p.E802fs 20/70 20/150 À10.50 À3.75 P33, F1976 P23§§ 53 M p.E754Ter HM HM NA NA P13, F476 P24§§ 61 M p.E754Ter HM HM À6.50 À6.00 P14, F476 BBS1¶¶ P25 16 M p.M390R/p.M390R 20/20 20/20 À1.50 À1.50 P377 P26 17 M p.R277K/p.I1389 del 20/1000 HM Plano Plano P27 21 M p.M390R/p.R483Ter 20/150 20/150 þ0.75 þ0.75 P28 22 F p.M390R/p.M390R 20/32 20/32 À4.00 À4.75 P29 24 F p.M390R/p.M390R 20/63 20/50 À3.25 À3.50 P177 P30 27 M p.M390R/p.M390R 10/200 12/200 À3.50 À3.50 P577 P31 29 F p.M390R/p.M390R 20/80 20/100 À4.75 À3.75 USH2A## P32 24 F p.C759F/p.W3955Ter 20/20 20/20 À0.25 À0.25 P258; F12, P178 P33 31 M p.Y1838Ter/p.C2128F 20/32 20/200 À1.50 À1.50 P34 41 M p.E767fs/p.N405fs 20/50 20/25 À0.25 Plano P358; F4, P179 P35 43 F p.C759F/p.V218E 20/20 20/20 À0.50 À0.50 P558; F16, P178 P36 62 M p.C759F/p.C759F 20/40 20/40 þ0.75 þ0.50 P37 81 F p.E767fs/p.E767fs LP LP þ13.75 þ14.00 HM, hand motions; LP, light perception; NA, not available; RE; right eye; LE, left eye. Novel mutation indicated in bold italics. † Best corrected visual acuity at first visit. ‡ Spherical equivalent. § Previous reports of phenotype and/or genotype, but neither the same data nor at same disease stage or patient age: Stone et al.,54 Huang et al.,76 Azari et al.,77 Jacobson et al.,58 Herrera et al.,78 and Schwartz et al.79 jj Numbering according to GenBank accession number NM_003322 starting at the translation initiation codon. ¶ §§Patients are siblings. # Numbering according to GenBank accession number NM_005906.4 starting at the translation initiation codon. ** Patients are cousins. ‡‡ Numbering according to GenBank accession number NM_001034853.1 starting at the translation initiation codon. ¶¶ Numbering according to GenBank accession number NM_024649 starting at the translation initiation codon. ## Numbering according to GenBank accession number NM_206933.2 starting at the translation initiation codon. clarified retinal degenerations (Table). All patients (and normal Imaging Studies—OCT subjects) underwent a complete eye examination. Informed consent was obtained from all subjects. Procedures adhered to Retinal OCT cross-sections were obtained with a spectral- the Declaration of Helsinki and were approved by the domain OCT system (RTVue-100; Optovue Inc., Fremont, CA, institutional review board. USA, and Bioptigen, Inc., Durham, NC, USA) in all TULP1-RD Downloaded from tvst.arvojournals.org on 09/26/2021 TULP1 and Other Ciliopathies IOVS j August 2014 j Vol.
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