DOCSLIB.ORG

Myopia and Late-Onset Progressive Cone Dystrophy Associate to LVAVA/MVAVA Exon 3 Interchange Haplotypes of Opsin Genes on Chromosome X

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Myopia and Late-Onset Progressive Cone Dystrophy Associate to LVAVA/MVAVA Exon 3 Interchange Haplotypes of Opsin Genes on Chromosome X Genetics Myopia and Late-Onset Progressive Cone Dystrophy Associate to LVAVA/MVAVA Exon 3 Interchange Haplotypes of Opsin Genes on Chromosome X Orsolya Orosz,1 Istv´an Rajta,2 Attila Vajas,1 Lili Tak´acs,1 Adrienne Csutak,1 Mariann Fodor,1 Bence Kolozsv´ari,1 Miklos´ Resch,3 Katalin Senyi,´ 3 Bal´azs Lesch,3 Viktoria´ Szabo,´ 3 Andr´as Berta,1 Istv´an Balogh,4 and Gergely Losonczy1,5 1Department of Ophthalmology, University of Debrecen, Debrecen, Hungary 2Institute for Nuclear Research, Hungarian Academy of Sciences, Debrecen, Hungary 3Department of Ophthalmology, Semmelweis University, Budapest, Hungary 4Division of Clinical Genetics, Department of Laboratory Medicine, University of Debrecen, Debrecen, Hungary 5Department of Ophthalmology, Zuyderland-Eyescan, Sittard-Geleen, The Netherlands Correspondence: Gergely Losonczy, PURPOSE. Rare interchange haplotypes in exon 3 of the OPN1LW and OPN1MW opsin genes Department of Ophthalmology, Uni- cause X-linked myopia, color vision defect, and cone dysfunction. The severity of the disease versity of Debrecen, H-4032, Na- varies on a broad scale from nonsyndromic high myopia to blue cone monochromatism. Here, gyerdei krt. 98, Debrecen, Hungary; we describe a new genotype–phenotype correlation attributed to rare exon 3 interchange [email protected]. haplotypes simultaneously present in the long- and middle-wavelength sensitive opsin genes Submitted: December 31, 2016 (L- and M-opsin genes). Accepted: February 28, 2017 METHODS. A multigenerational family with X-linked high myopia and cone dystrophy was Citation: Orosz O, Rajta I, Vajas A, et investigated. al. Myopia and late-onset progressive cone dystrophy associate to LVAVA/ RESULTS. Affected male patients had infantile onset myopia with normal visual acuity and color MVAVA exon 3 interchange haplotypes vision until their forties. Visual acuity decreased thereafter, along with the development of of opsin genes on chromosome X. severe protan and deutan color vision defects. A mild decrease in electroretinography Invest Ophthalmol Vis Sci. response of cone photoreceptors was detected in childhood, which further deteriorated in 2017;58:1834–1842. DOI:10.1167/ middle-aged patients. Rods were also affected, however, to a lesser extent than cones. Clinical iovs.16-21405 exome sequencing identified the LVAVA and MVAVA toxic haplotypes in the OPN1LW and OPN1MW opsin genes, respectively. CONCLUSION. Here, we show that LVAVA haplotype of the OPN1LW gene and MVAVA haplotype of the OPN1MW gene cause apparently nonsyndromic high myopia in young patients but lead to progressive cone–rod dystrophy with deuteranopia and protanopia in middle-aged patients corresponding to a previously unknown disease course. To the best of our knowledge, this is the first report on the joint effect of these toxic haplotypes in the two opsin genes on chromosome X. Keywords: X-linked high myopia, cone dystrophy, LVAVA he long- and middle-wavelength sensitive opsin genes (L- amino acids present at these locations. Normal opsin genes T and M-opsin genes; OPN1LW, OPN1MW, respectively) specify the haplotypes LVAIS and MVAIA in the L and M genes, reside in a head-to-tail tandem array on Xq28 and share 98% respectively. Toxic opsin variants that have been discovered in nucleotide identity.1 The normal gene array is composed of a human opsin-related diseases so far include LVAVA, LIAVA, locus control region (LCR), a single L gene followed by one or LIAVS, LIVVA, MVVVA, and MIAVA.4,11,26–31 Patients reported so more M genes with only the first two genes in the array far with an exon 3 interchange haplotype are summarized in expressed due to their proximity to the upstream cis-regulatory the Supplementary Material. Toxic exon 3 interchange haplo- LCR.2–5 Mutations in the LCR, L- (OPN1LW), and M- (OPN1MW) types have been commonly reported in BED.14,26,29,32–34 BED opsin genes on Xq28 lead to various X-linked cone-photore- was originally described in a family from the Danish island of ceptor disorders including red-green color vision defects Bornholm.32 The second family with BED from Minnesota had (Online Mendelian Inheritance in Man [OMIM] #303800 and also a Danish origin.14 Affected males had infantile onset #303900), X-linked cone dysfunction (Bornholm Eye Disease myopia with astigmatism, decreased visual acuity from child- [BED], OMIM #300843), X-linked cone dystrophy, and blue hood, subnormal photopic, and normal scotopic electroretino- cone monochromatism (BCM; OMIM #303700).1,4,6–25 Rare gram (ERG) parameters with normal macular appearance. The exon 3 interchange haplotypes are a recently described group disease showed no progression with age. The first family had a of mutations of the opsin genes on chromosome X, which deutan while the second had a protan color vision defect. The involve amino acid residues 153, 171, 174, 178, and 180, and disease was accounted for by the LVAVA interchange haplotype their name is the acronym of the one letter code of specific in one of the first two genes in the opsin gene array in both Copyright 2017 The Authors iovs.arvojournals.org j ISSN: 1552-5783 1834 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from iovs.arvojournals.org on 09/25/2021 Rare Opsin Haplotypes Cause Late-Onset Cone Dystrophy IOVS j March 2017 j Vol. 58 j No. 3 j 1835 families. This observation was the first to identify LVAVA acuity along with color vision deficiency in patients older than haplotype as a cause of BED.26 LVAVA haplotype associated to a 40 years. similar phenotype with either protan or deutan color vision defect in four individuals from four recently reported families.28 Rare interchange haplotypes have been shown to METHODS cause skipping of exon 3, a frame shift and premature termination of translation. However, in contrast to the LIAVA Patients and Ophthalmology Investigations haplotype, there was a residual low level of correctly spliced In the present study, we have investigated members of a three- opsin mRNA with the LVAVA or MIAVA haplotypes observed generation family with X-linked high-grade myopia. Autorefrac- indicating some amount of functionally normal opsin pro- 29,35 tometry was performed using a Topcon KR 8100 equipment teins. Accordingly, color vision defect was explained by (Topcon Corp., Tokyo, Japan). Color vision was tested under the lack of either L- or M-opsin genes in the first two positions standardized conditions, with pseudoisochromatic plates of the opsin gene array instead of a direct opsin inactivating 26 (Tafeln und Prufung¨ des Farbensinnes, 29. Auflage, 2002), effect in patients with the LVAVA haplotype. These observa- the Farnsworth Munsell 100-hue test and the anomaloscope tion suggests that the LVAVA haplotype has a dominant effect Nagel type II test. Color fundus photographs were taken with a on the development of myopia, a key element of BED, Zeiss FF450þIR fundus camera (Carl Zeiss AG, Jena, Germany) however, it is transcribed at a sufficient level to provide 26 mounted with a ZK-5 color sensor (Allied Vision Technologies normal opsin function. The strongest clinical evidence GmbH, Stadtroda, Germany) operated with Zeiss Visupack 4.4 supporting this hypothesis is the report on two Chinese software. Optical coherence tomography and confocal-scan- families with nonsyndromic high myopia associating to the 33,34 ning laser fundus autofluorescence (FAF) imaging was per- LVAVA haplotype. However, this represents a strikingly formed with Spectralis OCT (Heidelberg Engineering, different phenotype than observed in BED patients with the Heidelberg, Germany). Electroretinography was executed with same haplotype. Interestingly, the LVAVA haplotype is unique Ganzfeld Q400 equipment (Roland Consult GmbH, Branden- among interchange mutations in another aspect as well. burg, Germany) using standard International Society for According to its definition, BED is a nonprogressive disease. Clinical Electrophysiology of Vision parameters.36 Measures However, a spectral-domain optical coherence tomography of photoreceptor dysfunction were defined as: mild (70%–99% (SD-OCT) and adaptive optics scanning laser ophthalmoscopy of normal amplitude), moderate (30%–69% of normal), severe analysis of two patients with an LVAVA-only genotype showed (1%–29% of normal), or undetectable. The research was characteristic signs of progressive macular dystrophy including performed according to the Declaration of Helsinki and was overall retinal thinning, mottling of photoreceptor inner approved by the local institutional review boards. Written segments, and structural disruption of the inner retina and 27 informed consent was obtained from participating family the outer nuclear layer. This finding indicated that LVAVA members prior to investigation. haplotype causes progressive degenerative changes that result in damage to neighboring cells in addition to those expressing the mutated opsin. Moreover, these patients gradually devel- Isolation of Genomic DNA oped clinical signs of BED during their elementary school Genomic DNA was isolated from EDTA or citrate anticoagulat- years, representing a somewhat later disease onset than ed blood using the QIAamp Blood Mini kit according to the 27 observed in other BED patients. Taken together, our manufacturer’s instructions (Qiagen GmbH, Hilden, Germany). understanding on the genotype–phenotype correlation associ- ating to the LVAVA haplotype has largely developed since the first description of BED as a stationary disease with color vision
Load more

Recommended publications
  • The Vertebrate Retina Contains Two Types of Photoreceptors: Rods That
    JOURNAL OF NEUROCHEMISTRY | 2009 | 108 | 91–101 doi: 10.1111/j.1471-4159.2008.05739.x *Department of Anatomy, School of Medicine, Tokyo Women’s Medical University, Tokyo, Japan Genetics and Development Division, Toronto Western Research Institute, University Health Network, Department of Ophthalmology and Visual Sciences and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada àUniversity of Ottawa Eye Institute and Ottawa Health Research Institute, Ottawa, Ontario, Canada Abstract The retinas of staggerer mice, carrying a null mutation of Color vision is supported by retinal cone photoreceptors that, RORa, show significant down-regulation of Opn1sw, in most mammals, express two photopigments sensitive to Opn1mw, and Arr3. RORa acts in synergy with cone-rod short (S-opsin) or middle (M-opsin) wavelengths. Expression homeobox transcription factor (Crx), to activate the Opn1sw of the Opn1sw and Opn1mw genes, encoding S-opsin and promoter in vitro. Chromatin immunoprecipitation assays re- M-opsin, respectively, is under the control of nuclear veal that RORa directly binds to the Opn1sw promoter, receptors, including thyroid hormone receptor b2 (TRb2), Opn1mw locus control region, and the Arr3 promoter in vivo. retinoid X receptor c (RXRc), and RORb, a member of the Our data suggest that RORa plays a crucial role in cone retinoic acid receptor-related orphan receptor (ROR) family. development by directly regulating multiple cone genes. We now demonstrate that RORa, another member of the ROR Keywords: arrestin, cone photoreceptor, opsin, retina, family, regulates Opn1sw, Opn1mw, as well as Arr3 (cone RORa, staggerer. arrestin) in the mouse retina. RORa expression is detected in J.
    [Show full text]
  • Investigating Cone Photoreceptor Development Using Patient-Derived NRL Null Retinal Organoids
    ARTICLE https://doi.org/10.1038/s42003-020-0808-5 OPEN Investigating cone photoreceptor development using patient-derived NRL null retinal organoids Alyssa Kallman1,11, Elizabeth E. Capowski 2,11, Jie Wang 3, Aniruddha M. Kaushik4, Alex D. Jansen2, Kimberly L. Edwards2, Liben Chen4, Cynthia A. Berlinicke3, M. Joseph Phillips2,5, Eric A. Pierce6, Jiang Qian3, ✉ ✉ Tza-Huei Wang4,7, David M. Gamm2,5,8 & Donald J. Zack 1,3,9,10 1234567890():,; Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood. Treatment strategies would benefit from improved understanding of gene-expression patterns directing photoreceptor development, as many genes are implicated in both development and degeneration. Neural retina leucine zipper (NRL) is critical for rod photoreceptor genesis and degeneration, with NRL mutations known to cause enhanced S-cone syndrome and retinitis pigmentosa. While murine Nrl loss has been characterized, studies of human NRL can identify important insights for human retinal development and disease. We utilized iPSC organoid models of retinal development to molecularly define developmental alterations in a human model of NRL loss. Consistent with the function of NRL in rod fate specification, human retinal organoids lacking NRL develop S- opsin dominant photoreceptor populations. We report generation of two distinct S-opsin expressing populations in NRL null retinal organoids and identify MEF2C as a candidate regulator of cone development. 1 Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA. 2 Waisman Center, University of Wisconsin-Madison, Madison, USA. 3 Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, USA.
    [Show full text]
  • Intermixing the OPN1LW and OPN1MW Genes Disrupts the Exonic Splicing Code Causing an Array of Vision Disorders
    G C A T T A C G G C A T genes Review Intermixing the OPN1LW and OPN1MW Genes Disrupts the Exonic Splicing Code Causing an Array of Vision Disorders Maureen Neitz * and Jay Neitz Department of Ophthalmology and Vision Science Center, University of Washington, Seattle, WA 98109, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-206-543-7998 Abstract: Light absorption by photopigment molecules expressed in the photoreceptors in the retina is the first step in seeing. Two types of photoreceptors in the human retina are responsible for image formation: rods, and cones. Except at very low light levels when rods are active, all vision is based on cones. Cones mediate high acuity vision and color vision. Furthermore, they are critically important in the visual feedback mechanism that regulates refractive development of the eye during childhood. The human retina contains a mosaic of three cone types, short-wavelength (S), long-wavelength (L), and middle-wavelength (M) sensitive; however, the vast majority (~94%) are L and M cones. The OPN1LW and OPN1MW genes, located on the X-chromosome at Xq28, encode the protein component of the light-sensitive photopigments expressed in the L and M cones. Diverse haplotypes of exon 3 of the OPN1LW and OPN1MW genes arose thru unequal recombination mechanisms that have intermixed the genes. A subset of the haplotypes causes exon 3- skipping during pre-messenger RNA splicing and are associated with vision disorders. Here, we review the mechanism by which splicing defects in these genes cause vision disorders. Citation: Neitz, M.; Neitz, J.
    [Show full text]
  • Jpet #245167 1
    JPET Fast Forward. Published on November 21, 2017 as DOI: 10.1124/jpet.117.245167 This article has not been copyedited and formatted. The final version may differ from this version. JPET #245167 TITLE PAGE A combination of G protein-coupled receptor modulators protects photoreceptors from degeneration Tivadar Orban, Henri Leinonen, Tamar Getter, Zhiqian Dong, Wenyu Sun, Songqi Gao, Downloaded from Alexander Veenstra, Hossein Heidari-Torkabadi, Timothy S. Kern, Philip D. Kiser, and Krzysztof Palczewski jpet.aspetjournals.org Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA (T.O., H. L., S. Q., at ASPET Journals on September 24, 2021 S. G., T. G., A. V., H. H-T., T. S. K., P. D. K., K. P.) Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA (T. S. K., P. D. K.) Polgenix Inc., Cleveland, OH 44106, USA (Z. D., W. S.) 1 JPET Fast Forward. Published on November 21, 2017 as DOI: 10.1124/jpet.117.245167 This article has not been copyedited and formatted. The final version may differ from this version. JPET #245167 RUNNING TITLE PAGE RUNNING TITLE: Drugs protective against retinal rod and cone degeneration. CORRESPONDENCE Krzysztof Palczewski, Dept. of Pharmacology, School of Medicine, Case Western Reserve Downloaded from University, 10900 Euclid Ave., Cleveland, OH 44106. Tel.: 216-368-4631; Fax: 216-368-1300; E-mail: [email protected] jpet.aspetjournals.org MANUSCRIPT STATISTICS Text Pages: 41 at ASPET Journals on September 24, 2021 Tables: 1 Figures: 8 References: 36 Abstract Length: 248 words Introduction Length: 742 words Discussion Length: 1436 words 2 JPET Fast Forward.
    [Show full text]
  • Intermixing the OPN1LW and OPN1MW Genes Disrupts the Exonic Splicing Code Causing an Array of Vision Disorders
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 8 July 2021 doi:10.20944/preprints202107.0202.v1 Review Intermixing the OPN1LW and OPN1MW Genes Disrupts the Exonic Splicing Code Causing an Array of Vision Disorders Neitz, Maureen 1,*, Neitz, Jay 1 1 University of Washington, Vision Sciences Center [email protected] * Correspondence: [email protected]; Tel.: +1-206-543-7998 Abstract: The first step in seeing is light absorption by photopigment molecules expressed in the photoreceptors of the retina. There are two types of photoreceptors in the human retina that are responsible for image formation, rods and cones. Except at very low light levels when rods are active, all vision is based on cones. Cones mediate high acuity vision and color vision. Further- more, they are critically important in the visual feedback mechanism that regulates refractive de- velopment of the eye during childhood. The human retina contains a mosaic of three cone types, short-wavelength (S), long-wavelength (L) and middle-wavelength (M); however, the vast major- ity (~94%) are L and M cones. The OPN1LW and OPN1MW genes, located on the X-chromosome at Xq28, encode the protein component of the light-sensitive photopigments. Here we review mechanism by which splicing defects in these genes cause vision disorders. Keywords: colorblindness, color vision, myopia, cone photopigment, exon skipping, X-linked cone dysfunction 1. Introduction Cone photoreceptors contain light sensitive photopigments comprised of an apo- protein component termed opsin, and a covalently bound chromophore, 11-cis reti- nal. The human S cone opsin gene, OPN1SW resides on chromosome 6, while the L and M cone opsin genes, OPN1LW and OPN1MW, are located on the X-chromosome at Xq28.
    [Show full text]
  • Datasheet Blank Template
    SAN TA C RUZ BI OTEC HNOL OG Y, INC . OPN1MW/LW (C-19): sc-14358 BACKGROUND PRODUCT G protein-coupled receptors (GPCRs), which are characterized by containing Each vial contains 200 µg IgG in 1.0 ml of PBS with < 0.1% sodium azide seven transmembrane α helices, elicit G protein-mediated signaling cas cades and 0.1% gelatin. in response to a variety of stimuli. The opsin subfamily, which represents Blocking peptide available for competition studies, sc-14358 P, (100 µg approximately 90 percent of all GPCRs, is comprised of photoreceptors that peptide in 0.5 ml PBS containing < 0.1% sodium azide and 0.2% BSA). are activated by light. It includes the red-, green- and blue-sensitive opsins and rhodopsin. The opsin subfamily consists of an apoprotein covalently linked APPLICATIONS to 11 -cis- retinal, which undergoes isomerization upon the absorption of pho - tons. This isomerization leads to a conformational change of the protein, OPN1MW/LW (C-19) is recommended for detection of the opsin proteins which results in the activation of hundreds of G proteins. Color is perceived encoded by OPN1MW and OPN1LW of human origin, and the opsin protein in humans by three pigments, which localize to retinal cone photoreceptor encoded by Opn1mw of mouse and rat origin by Western Blotting (starting cells. Mutations in the gene encoding OPN1MW and OPN1MW2 are the dilution 1:200, dilution range 1:100-1:1000), immunofluorescence (starting cause of deutanopic colorblindness, whereas OPN1LW gene mutations lead dilution 1:50, dilution range 1:50-1:500) and solid phase ELISA (starting to protanopic colorblindness.
    [Show full text]
  • (Raav)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays
    International Journal of Molecular Sciences Review Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays Thilo M. Buck 1 and Jan Wijnholds 1,2,* 1 Department of Ophthalmology, Leiden University Medical Center (LUMC), 2333 ZC Leiden, The Netherlands; [email protected] 2 Netherlands Institute of Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands * Correspondence: [email protected]; Tel.: +31-71-52-69269 Received: 20 May 2020; Accepted: 10 June 2020; Published: 12 June 2020 Abstract: Inherited retinal dystrophies and optic neuropathies cause chronic disabling loss of visual function. The development of recombinant adeno-associated viral vectors (rAAV) gene therapies in all disease fields have been promising, but the translation to the clinic has been slow. The safety and efficacy profiles of rAAV are linked to the dose of applied vectors. DNA changes in the rAAV gene cassette affect potency, the expression pattern (cell-specificity), and the production yield. Here, we present a library of rAAV vectors and elements that provide a workflow to design novel vectors. We first performed a meta-analysis on recombinant rAAV elements in clinical trials (2007–2020) for ocular gene therapies. We analyzed 33 unique rAAV gene cassettes used in 57 ocular clinical trials. The rAAV gene therapy vectors used six unique capsid variants, 16 different promoters, and six unique polyadenylation sequences. Further, we compiled a list of promoters, enhancers, and other sequences used in current rAAV gene cassettes in preclinical studies. Then, we give an update on pro-viral plasmid backbones used to produce the gene therapy vectors, inverted terminal repeats, production yield, and rAAV safety considerations.
    [Show full text]
  • Color Vision Deficiency
    Color vision deficiency Description Color vision deficiency (sometimes called color blindness) represents a group of conditions that affect the perception of color. Red-green color vision defects are the most common form of color vision deficiency. Affected individuals have trouble distinguishing between some shades of red, yellow, and green. Blue-yellow color vision defects (also called tritan defects), which are rarer, cause problems with differentiating shades of blue and green and cause difficulty distinguishing dark blue from black. These two forms of color vision deficiency disrupt color perception but do not affect the sharpness of vision (visual acuity). A less common and more severe form of color vision deficiency called blue cone monochromacy causes very poor visual acuity and severely reduced color vision. Affected individuals have additional vision problems, which can include increased sensitivity to light (photophobia), involuntary back-and-forth eye movements (nystagmus) , and nearsightedness (myopia). Blue cone monochromacy is sometimes considered to be a form of achromatopsia, a disorder characterized by a partial or total lack of color vision with other vision problems. Frequency Red-green color vision defects are the most common form of color vision deficiency. This condition affects males much more often than females. Among populations with Northern European ancestry, it occurs in about 1 in 12 males and 1 in 200 females. Red- green color vision defects have a lower incidence in almost all other populations studied. Blue-yellow color vision defects affect males and females equally. This condition occurs in fewer than 1 in 10,000 people worldwide. Blue cone monochromacy is rarer than the other forms of color vision deficiency, affecting about 1 in 100,000 people worldwide.
    [Show full text]
  • Supplemental Material
    Supplemental material Systems Pharmacology Approach to Prevent Retinal Degeneration in Stargardt Disease Yu Chen, Grazyna Palczewska, Debarshi Mustafi, Marcin Golczak, Zhiqian Dong, Osamu Sawada, Tadao Maeda, Akiko Maeda, and Krzysztof Palczewski Table of Contents: 1. Supplemental Table 1. 2. Supplemental Table 2. 3. Supplemental Table 3. 4. References. 1 Supplemental Table 1. Expression of GPCRs in the eye and retina of C57BL/6J mice and the retina of a human donor eye (normalized FPKM values)A. Genes B6 mouse B6 mouse Human retina eye retina Rho 6162.04 11630.18 6896.09 Rgr 355.74 97.66 123.98 Opn1sw 125.13 198.54 31.69 Drd4 93.84 241.78 139.49 Opn1mw 62.97 95.77 172.56 Gprc5b 29.82 12.95 22.85 Gpr162 29.37 73.32 46.29 Gpr37 28.47 41.28 66.65 Ednrb 22.27 1.94 5.77 Rorb 21.69 23.52 24.31 Gpr153 20.42 37.18 15.31 Gabbr1 19.78 40.24 35.38 Rrh 19.29 9.23 40.34 2 Gpr152 18.55 40.46 3.05 Adora1 16.20 18.26 13.55 Lphn1 15.98 29.73 31.85 Tm2d1 15.56 10.31 17.63 Cxcr7 14.30 3.58 2.37 Ppard 13.68 19.37 21.61 Agtrap 13.64 17.21 8.18 Cd97 12.93 1.77 1.55 Gpr19 12.21 8.45 1.11 Fzd1 11.99 3.29 7.35 Fzd6 11.34 1.85 2.76 Gpr87 11.34 0.04 0.00 Lgr4 11.09 9.50 18.07 Drd2 10.82 23.10 26.33 Smo 10.75 6.35 5.91 S1pr1 10.66 11.21 11.78 Bai1 10.08 27.10 10.82 3 Glp2r 9.94 34.85 0.31 Ptger1 9.59 14.88 0.94 Gpr124 9.56 8.94 19.82 F2r 9.31 5.32 0.15 Adra2c 8.96 7.17 2.38 Gpr146 8.91 7.49 6.17 Vipr2 8.79 14.33 10.69 Fzd5 8.69 10.01 7.73 Gpr110 8.59 0.08 0.02 Adrb1 8.43 20.18 3.84 S1pr3 8.42 6.95 3.56 Gabbr2 7.80 17.03 10.57 Lphn2 7.66 9.02 8.79 Lpar1 7.47 0.91
    [Show full text]
  • Substitution of Isoleucine for Threonine at Position 190 of S-Opsin Causes S-Cone-Function Abnormalities ⇑ Rigmor C
    Vision Research 73 (2012) 1–9 Contents lists available at SciVerse ScienceDirect Vision Research journal homepage: www.elsevier.com/locate/visres Substitution of isoleucine for threonine at position 190 of S-opsin causes S-cone-function abnormalities ⇑ Rigmor C. Baraas a, , Lene A. Hagen a, Elise W. Dees a, Maureen Neitz b a Department of Optometry & Visual Science, Buskerud University College, 3603 Kongsberg, Norway b Department of Ophthalmology, University of Washington Medical School, Seattle, WA 98195, USA article info abstract Article history: Five mutations in the S-cone–opsin gene (OPN1SW) that give rise to different single amino-acid substi- Received 15 October 2011 tutions (L56P, G79R, S214P, P264S, R283Q) are known to be associated with tritan color-vision deficiency. Received in revised form 30 August 2012 Here we report a sixth OPN1SW mutation (T190I) and the associated color vision phenotype. S-opsin Available online 26 September 2012 genotyping and clinical evaluation of color vision were performed on affected and unaffected family members and normal controls. Chromatic contrast was tested at different levels of retinal illuminance. Keywords: Affected family members were heterozygous for a nucleotide change that substituted the amino acid iso- Tritan color-vision deficiency leucine (I) in place of threonine (T) that is normally present at position 190 of the S-opsin. The mutation is Rod–cone interaction in extracellular loop II (EII). The association between making tritan errors and having the T190I mutant S S-opsin mutation opsin was strong (p > 0.0001: Fisher’s exact test). The performance of subjects with the T190I mutation was significantly different from that of normal trichromats along the tritan vector under all conditions tested (Mann–Whitney U: p < 0.05), but not along the protan or deutan vectors.
    [Show full text]
  • The Molecular and Cellular Basis of Rhodopsin Retinitis Pigmentosa Reveals Potential Strategies for Therapy
    The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy. Dimitra Athanasiou1, Monica Aquila1, James Bellingham1, Wenwen Li1, Caroline McCulley1, Philip J. Reeves2*, anD Michael E. Cheetham1* 1UCL Institute of Ophthalmology, 11-43 Bath Street, LonDon EC1V 9EL, UK 2School of Biological Sciences, University of Essex, Wivenhoe Park, Essex CO4 3SQ, UK *CorresponDence shoulD be aDDresseD to Professor Mike Cheetham, [email protected] or Dr Phil Reeves, [email protected] Keywords rhoDopsin, GPCR, retinal Dystrophy, neuroDegeneration, mutation, protein misfolDing, proteostasis, therapy, protein traffic, enDocytosis, CRISPR 1 Contents Page Title page 1 Contents 2 Abbreviations 4 Glossary 6 Abstract 7 1. IntroDuction 8 1.1 IDentification of mutations in rhoDopsin (RHO) 8 1.2 Phenotypes of rhoDopsin associateD retinal Dystrophies 9 1.2.1 CSNB 10 1.2.2 arRP 11 1.2.3 aDRP 11 1.3 Variation in the RHO gene, when is a variant a mutation? 12 2. Structural anD biochemical basis of rhoDopsin RP mutants 14 2.1 Why so many Dominant rhoDopsin RP mutants? 14 2.2 The Distribution of RP mutants in rhoDopsin 15 2.2.1 RP mutations locateD in the N-terminus of rhoDopsin: the role of the N- terminal cap 15 2.2.2 RP mutations in the transmembrane helices 18 2.3 Structural stuDies of CSNB mutants 19 2.4 Dimerization Deficiency in adRP mutants 20 3. RhoDopsin biogenesis, post-translational moDifications anD trafficking 21 3.1 MisfolDing, ER retention anD instability 22 3.2 Post Golgi trafficking anD OS targeting 24 3.3 DisrupteD vesicular traffic anD enDocytosis 26 3.4 AltereD post-translational moDifications anD reDuceD stability 27 3.5 AltereD transducin activation 28 3.6 Constitutive activation 28 4.
    [Show full text]
  • Identification of Potential Molecular Targets Associated with Proliferative
    Shao et al. BMC Ophthalmology (2020) 20:143 https://doi.org/10.1186/s12886-020-01381-5 RESEARCH ARTICLE Open Access Identification of potential molecular targets associated with proliferative diabetic retinopathy Dewang Shao1,2*, Shouzhi He1,ZiYe1, Xiaoquan Zhu2, Wei Sun2, Wei Fu2, Tianju Ma1 and Zhaohui Li1* Abstract Background: This study aimed to identify and evaluate potential molecular targets associated with the development of proliferative diabetic retinopathy (DR). Methods: The microarray dataset “GSE60436” generated from fibrovascular membranes (FVMs) associated with proliferative DR was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) from the active FVMs and control or inactive FVMs and control were evaluated and co-DEGs were identified using VEEN analysis. Functional enrichment analysis, and protein-protein interactions (PPI) network and module analyses were performed on the upregulated and downregulated coDEGs. Finally, several predictions regarding microRNAs (miRNAs) and transcription factors (TFs) were made to construct a putative TF-miRNA-target network. Results: A total of 1475 co-DEGs were screened in active/inactive FVM samples, including 461 upregulated and 1014 downregulated genes, which were enriched for angiogenesis [Hypoxia Inducible Factor 1 Subunit Alpha (HIF1A) and Placental Growth Factor (PGF)] and visual perception, respectively. In the case of the upregulated co-DEGs, Kinesin Family Member 11 (KIF11), and BUB1 Mitotic Checkpoint Serine/Threonine Kinase (BUB1) exhibited the highest values in both the PPI network and module analyses, as well as the genes related to mitosis. In the case of downregulated co-DEGs, several G protein subunits, including G Protein Subunit Beta 3 (GNB3), exhibited the highest values in both the PPI network and module analyses.
    [Show full text]