Search

Sriganesh Ramachandra Rao, Lara A. Skelton, Fuguo Wu, Agnieszka Onysk, Grzegorz Spolnik, Witold Danikiewicz, Mark C. Butler, Delores A. Stacks, Liliana Surmacz, Xiuqian Mu, Ewa Swiezewska, Steven J. Pittler, Steven J. Fliesler | iScience | Vol 23, Issue 6 | June 2020 26 |  doi.org/10.1016/j.isci.2020.101198 Summary Dehydrodolichyl diphosphate synthase (DHDDS) catalyzes the committed step in dolichol synthesis. Recessive mutations in DHDDS cause retinitis pigmentosa (RP59), resulting in blindness. We hypothesized that rod photoreceptor-specific ablation of Dhdds would cause retinal degeneration due to diminished dolichol-dependent protein N -glycosylation. Dhdds flx/flx mice were crossed with rod-specific Cre recombinase-expressing (Rho-iCre75) mice to generate rod-specific Dhdds knockout mice ( Dhdds flx/flx iCre+). In vivo morphological and electrophysiological evaluation of Dhdds flx/flx iCre+ retinas revealed mild retinal dysfunction at postnatal (PN) 4 weeks, compared with age-matched controls; however, rapid photoreceptor degeneration ensued, resulting in almost complete loss of rods and cones by PN 6 weeks. Retina dolichol levels were markedly decreased by PN 4 weeks in Dhdds flx/flx iCre+ mice, relative to controls; despite this, N -glycosylation of retinal proteins , including opsin (the dominant rod-specific glycoprotein), persisted in Dhdds flx/flx iCre+ mice. These findings challenge the conventional mechanistic view of RP59 as a congenital disorder of glycosylation . Introduction Retinitis pigmentosa (RP) represents a large class of inherited retinal dystrophies caused by mutations in several families of genes, leading to pigmentary retinopathy and progressive, irreversible blindness. Typically, RP is characterized by the initial loss of rod photoreceptors (PRs), deposition of pigment granules, and peripheral vision loss ( Ferrari et al., 2011 , Hamel, 2006 ). Defective asparagine-linked glycosylation ( N -glycosylation) of proteins in rod cells, particularly the visual pigment rhodopsin (RHO), results in progressive, irreversible rod cell degeneration and death, with concomitant loss of vision ( Murray et al., 2009 , Murray et al., 2015 , Kaushal et al., 1994 , Fliesler et al., 1984a ). Successful glycosylation of RHO is necessary for its vectorial trafficking through the inner segment (cell body) of the rod cell to the site of rod outer segment (ROS) membrane assembly at the base of the ROS. Retinal degeneration has been observed in patients harboring RHO mutations involving the N -glycosylation consensus sites, and in animal models involving comparable RHO mutations ( Van Den Born et al., 1994 , Zhu et al., 2004 , Sullivan et al., 1993 , Murray et al., 2015 , Iwabe et al., 2016 ), as well as by tunicamycin-induced and genetic inhibition of global/RHO N -glycosylation ( Fliesler and Basinger, 1985 , Fliesler et al., 1985 , Sabry et al., 2016 , Thompson et al., 2013 , Murray et al., 2015 ). Protein N -glycosylation involves the following steps (schematic representation, Figure 1 ): generation of dolichol (Dol, an important isoprenoid arising from the mevalonate pathway) and dolichyl phosphate (Dol-P, the obligate glycan carrier necessary for N -linked glycosylation, O -mannosylation, and C -mannosylation) ( Burda and Aebi, 1999 , Endo et al., 2003 , Park et al., 2014 , Cantagrel et al., 2010 , Burton et al., 1979 , Maeda et al., 2000 , Doucey et al., 1998 ), generation of complex Dol-P-linked oligosaccharides (DLO) ( Krasnova and Wong, 2016 , Gandini et al., 2017 , Behrens and Leloir, 1970 ), and transfer of those oligosaccharides from DLO to the N -glycosylation consensus site on the target polypeptide ( Welply et al., 1983 ). Genetic defects affecting the glycosylation mechanism constitute a large family of syndromes termed “congenital disorders of glycosylation” (CDGs), with more than 150 causative genes ( Ng and Freeze, 2018 , Sparks and Krasnewich, 1993 ). A family of genetic diseases pertaining to Dol synthesis is classified as CDG-I (the class of CDG involving defective glycan assembly and/or their transfer in the endoplasmic reticulum [ER]) due to the requirement of DLO for N -glycosylation. Common clinical features of CDGs include failure to thrive, retarded development, protein-losing enteropathy, early-onset encephalopathy, as well as retinopathies such as RP ( Sparks and Krasnewich, 1993 , Thompson et al., 2013 , Hamdan et al., 2017 , Morava et al., 2009 ).

A new gene therapy has been used to treat patients with a rare inherited eye disorder which causes blindness. It's hoped the NHS treatment will halt sight loss and even improve vision. Matthew Wood, 48, one of the first patients to receive the injection, told the BBC: "I value the remaining sight I have so if I can hold on to that it would be a big thing for me." The treatment costs around £600,000 but NHS England has agreed a discounted price with the manufacturer Novartis. Luxturna (voretigene neparvovec), has been approved by The National Institute for Health and Care Excellence (NICE), which estimates that just under 90 people in England will be eligible for the treatment. The gene therapy is for patients who have retinal dystrophy as a result of inheriting a faulty copy of the RPE65 gene from both parents. The gene is important for providing the pigment that light sensitive cells need to absorb light. Initially this affects night vision but eventually, as the cells die, it can lead to complete blindness. Read more . . .

By Patricia C Sanchez Diaz, DVM, PhD, FAAO Purpose This report aims to illustrate the impact of genetic testing in the diagnosis and management of hereditary retinal dystrophy. Here we describe the genetic changes identified in the USH2A gene in three patients with a clinical diagnosis of Usher syndrome (RP plus hearing loss) and discuss the implications of these genetic findings in helping patients to better understand their condition and to plan for their future. Read more

Changyi Ji , Yao Li , Alec Kittredge , Austin Hopiavuori , Nancy Ward , Peng Yao , Yohta Fukuda , Yu Zhang , Stephen H. Tsang , Tingting Yang  | Scientific Reports | Vol 9 | 19026 | 13 Dec 2019 | https://doi.org/10.1038/s41598-019-54892-7 Abstract BEST1 is a Ca2+-activated Cl− channel predominantly expressed in retinal pigment epithelium (RPE), and over 250 genetic mutations in the BEST1 gene have been identified to cause retinal degenerative disorders generally known as bestrophinopathies. As most BEST1 mutations are autosomal dominant, it is of great biomedical interest to determine their disease-causing mechanisms and the therapeutic potential of gene therapy. Here, we characterized six Best vitelliform macular dystrophy (BVMD)-associated BEST1 dominant mutations by documenting the patients’ phenotypes, examining the subcellular localization of endogenous BEST1 and surface Ca2+-dependent Cl− currents in patient-derived RPEs, and analyzing the functional influences of these mutations on BEST1 in HEK293 cells. We found that all six mutations are loss-of-function with different levels and types of deficiencies, and further demonstrated the restoration of Ca2+-dependent Cl− currents in patient-derived RPE cells by WT BEST1 gene supplementation. Importantly, BEST1 dominant and recessive mutations are both rescuable at a similar efficacy by gene augmentation via adeno-associated virus (AAV), providing a proof-of-concept for curing the vast majority of bestrophinopathies. Introduction Genetic mutation of the human BEST1 gene causes bestrophinopathies, which consist of a spectrum of retinal degeneration disorders including Best vitelliform macular dystrophy (BVMD) 1 , 2 , autosomal recessive bestrophinopathy (ARB) 3 , adult-onset vitelliform dystrophy (AVMD) 4 , 5 , autosomal dominant vitreoretinochoroidopathy (ADVIRC) 6 , and retinitis pigmentosa (RP) 7 . BVMD, featuring an early-onset and debilitating form of central macular degeneration, is the most common bestrophinopathy. Due to abnormalities in the fluid and/or electrolyte homeostasis between the RPE and photoreceptor outer segments 8 , the disease leads to the formation of serous retinal detachment and lesions that resemble egg yolk, or vitelliform, while rod and cone photoreceptor function remains unaffected. All types of bestrophinopathies, except for ARB, result from autosomal dominant mutation of BEST1 . Patients are susceptible to untreatable, progressive vision loss, which significantly deteriorates life quality. Therefore, understanding the mechanisms of BEST1 disease-causing mutations and designing strategies to restore the damaged cellular function are critical for developing treatments for bestrophinopathies. The protein encoded by the BEST1 gene is a Cl− channel named BESTROPHIN1 (BEST1), which is activated in response to intracellular Ca2+ and conducts Ca2+-dependent Cl− current on the cell membrane of retinal pigment epithelium (RPE) 1 , 2 , 9 , 10 . Consistently, Ca2+-dependent Cl− current has been suggested to generate a critical visual response upon light exposure, namely light peak (LP) 11 , 12 , 13 , which is defective in almost all BEST1 -mutated patients as shown by electrooculography (EOG) 14 , 15 . This BEST1- Cl− current- LP correlation suggests gene supplementation as a promising approach for curing bestrophinopathies. Indeed, we reported that the impaired Cl− current in RPE derived from an ARB patient bearing a BEST1 recessive mutation was rescuable by baculovirus (BV) -mediated supplementation of the WT BEST1 gene 9 . Moreover, a recent study in canine models demonstrated that the retinal abnormalities caused by recessive mutation of BEST1 can be corrected by adeno-associated virus (AAV) -mediated subretinal BEST1 gene augmentation 16 . However, the rescue efficacy of gene augmentation for BEST1 dominant mutations is still unknown. This is a very important question because firstly, most of BEST1 mutations are dominant, and secondly, it will determine whether disruption/suppression of the dominant mutant allele is necessary in therapeutic interventions. In principle, the excess of WT BEST1 could overwhelm the mutant BEST1 despite the latter being dominant over the former at a 1:1 ratio. As canines do not have BEST1 dominant mutation genotypes while Best1 knockout mice do not show any retinal phenotype or Cl− current abnormality 17 , 18 , patient-derived RPEs offer a more relevant model for testing the rescue of BEST1 dominant mutations. Here, we analyzed six BEST1 dominant mutations from BVMD patients, namely p.A10T, p.R218H, p.L234P, p.A243T, p.Q293K and p.D302A, using clinical examinations, patient-derived RPEs, electrophysiological recordings and structural models. Our results showed that these mutations are all loss-of-function with complete or partial deficiency of channel activity, while some of them affect the subcellular localization and/or Ca2+-sensitivity of BEST1. Remarkably, defective Ca2+-dependent Cl− currents in patient-derived RPE cells were restored by virus-mediated supplementation of the WT BEST1 gene in a time- and dose-dependent manner. Moreover, both dominant and recessive mutations of BEST1 are rescuable at a similar efficacy, and both BV and AAV can be used as the vector for gene delivery. Together, our findings underscore the great potential of gene augmentation therapy in treating bestrophinopathies, including those caused by BEST1 dominant mutations. Results Retinal phenotypes of six BVMD patients with different BEST1 mutations We examined six BVMD patients from unrelated families. Generalized retinal dysfunction was found in all six patients. Fundus autofluorescence imaging and optical coherence tomography (OCT) revealed vitelliform lesions located in the subretinal space, as well as serous retinal detachments and cystic fluid in the maculae area (Fig.  1 and Supplementary Fig.  S1 ). Unlike BEST1 recessive patients, whose electroretinography (ERG) and EOG results are significantly different from WT people 9 , BVMD patients display normal ERG but abnormal EOG results (Supplementary Fig.  S2 ) 19 . Click here to read entire article References Marquardt, A. et al . Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best’s disease). Human molecular genetics 7, 1517–1525 (1998). Petrukhin, K. et al . Identification of the gene responsible for Best macular dystrophy. Nature genetics 19, 241–247 (1998). Burgess, R. et al . Biallelic mutation of BEST1 causes a distinct retinopathy in humans. American journal of human genetics 82, 19–31 (2008). Allikmets, R. et al . Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies. Hum Genet 104, 449–453 (1999). Kramer, F. et al . Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration. Eur J Hum Genet 8, 286–292 (2000). Yardley, J. et al . Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). Investigative ophthalmology & visual science 45, 3683–3689 (2004). Davidson, A. E. et al . Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa. American journal of human genetics 85, 581–592 (2009). Yang, T., Justus, S., Li, Y. & Tsang, S. H. BEST1: the Best Target for Gene and Cell Therapies. Molecular therapy: the journal of the American Society of Gene Therapy 23, 1805–1809 (2015). Li, Y. et al . Patient-specific mutations impair BESTROPHIN1′s essential role in mediating Ca2+-dependent Cl- currents in human RPE. Elife , https://doi.org/10.7554/eLife.29914 (2017). Marmorstein, A. D. et al . Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proc Natl Acad Sci USA 97, 12758–12763 (2000). Fujii, S., Gallemore, R. P., Hughes, B. A. & Steinberg, R. H. Direct evidence for a basolateral membrane Cl- conductance in toad retinal pigment epithelium. The American journal of physiology 262, C374–383 (1992). Gallemore, R. P. & Steinberg, R. H. Effects of DIDS on the chick retinal pigment epithelium. II. Mechanism of the light peak and other responses originating at the basal membrane. J Neurosci 9, 1977–1984 (1989). Gallemore, R. P. & Steinberg, R. H. Light-evoked modulation of basolateral membrane Cl- conductance in chick retinal pigment epithelium: the light peak and fast oscillation. Journal of neurophysiology 70, 1669–1680 (1993). Boon, C. J. et al . The spectrum of ocular phenotypes caused by mutations in the BEST1 gene. Progress in retinal and eye research 28, 187–205 (2009). Marmorstein, A. D., Cross, H. E. & Peachey, N. S. Functional roles of bestrophins in ocular epithelia. Progress in retinal and eye research 28, 206–226 (2009). Guziewicz, K. E. et al . BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure. Proc Natl Acad Sci USA 115, E2839–E2848 (2018). Marmorstein, L. Y. et al . The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1). J Gen Physiol 127, 577–589 (2006). Milenkovic, A. et al . Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells. Proc Natl Acad Sci USA 112, E2630–2639 (2015). Johnson, A. A. et al . Bestrophin 1 and retinal disease. Progress in retinal and eye research . https://doi.org/10.1016/j.preteyeres.2017.01.006 (2017).

Imran H Yusuf, Johannes Birtel, Morag Shanks, Penny Clouston, Susan M. Downes, Peter Charbel Issa, Robert E MacLaren Abstract Purpose : SNRNP200 is a gene recently identified as a cause of autosomal dominant retinitis pigmentosa (RP). The aim of this study was to report novel disease-associated variants and describe the retinal phenotype in patients with RP due to variants in SNRNP200, a gene encoding a ubiquitously expressed protein important in pre-mRNA splicing. Methods : A cross-sectional descriptive study involving patients identified from two tertiary referral retinal genetics clinics. 9 consecutive patients from 8 families with RP attributed to variants in SNRNP200 were included. Genetic diagnoses were established with molecular genetic testing using targeted next-generation sequencing. All patients underwent full clinical ophthalmic evaluation, retinal imaging with spectral-domain optical coherence tomography, short wavelength fundus autofluorescence (Heidelberg Spectralis) and digital colour fundus photography. Results : 9 patients were included in the study, 4 of whom were female, aged between 16 and 55 years of age. Each patient presented with symptoms and signs typical of a rod-cone dystrophy. Retinal imaging characteristics are presented in Figure 1. There was no suggestion of any systemic or syndromic features. Disease onset was commonly seen in childhood, although two patients experienced symptom onset in middle age (range 4 to 53 years). Progression of retinal degeneration was slow: 7 patients had a best corrected visual acuity of better than 20/40 in the better seeing eye at last follow-up (age 16 to 55), although two patients developed macular oedema. Molecular genetic testing revealed 2 novel variants (c.1547G>T p.(Cys516Phe) and c.2359G>A p.(Ala787Thr)) and 7 previously described variants in SNRNP200, all of which were missense variants. Both novel variants are well conserved, segregate with disease in affected families and are predicted to be disease causing in silico. Conclusions : Variants in SNRNP200 result in non-syndromic rod-cone dystrophy characterized clinically by a variable age of symptom onset with a retinal phenotype typical of RP. This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019. Read the original article.

Andrew P. Schachat MD, in Ryan's Retina, 2018 USH Interactome The USH genes encode proteins of different classes and families, including motor proteins, scaffold proteins, cell adhesion molecules and transmembrane receptor proteins. In vitro direct interaction studies between USH proteins and also localization studies in mouse models have, however, suggested functional relationships between these proteins such that an “USH interactome” has been proposed.606 In these studies, it should be noted, however, that although all the USH mouse models show severe hearing loss and vestibular dysfunction, only the Ush2A-/- mouse, shows signs of RP.607 From such work, a “multiprotein scaffold complex” model has been proposed for harmonin, whirlin, and sans. There is also evidence that harmonin and whirlin can bind all other components of the USH network, including cadherin 23, protocadherin 15, usherin, VLGR1 and myosinVIIA.569,603,608 Click here to read source article

Artur V. Cideciyan, Raghavi Sudharsan, Valérie L. Dufour, Michael, T. Massengill, Simone Iwabe, Malgorzata Swider, BriannaLisi, Alexander Sumaroka, Luis Felipe Marinho, Tatyana Appelbaum, Brian Rossmiller, William W. Hauswirth, Samuel G.Jacobson, Alfred S. Lewin, Gustavo D. Aguirre, William A. Beltran | Edited by Jeremy Nathans, Johns Hopkins University, Baltimore, MD | August 20, 2018 | 115 (36) E8547-E8556 | https://doi.org/10.1073/pnas.1805055115 Article Summary A number of gene-augmentation strategies are entering clinical trials for the treatment of inherited retinal blindness. Gene therapy for autosomal dominant diseases faces significant obstacles that include allelic heterogeneity and the potential need to silence the mutated gene. Here we show that a single-gene therapy vector that combines knockdown of the causative gene with its replacement by a resistant wild-type copy can prevent photoreceptor cell death and vision loss in a canine model of autosomal dominant retinitis pigmentosa. Read more, click here

Joanna Monika Gray ,  Harry Otway Orlans ,  Morag Shanks ,  Penny Clouston ,  Robert Elvis MacLaren   | Ophthalmic Genetics | 21 May 2018 | Volume 39(4) | pages 508-511 | doi: 10.1080/13816810.2018.1474369 Background The growing number of clinical trials currently underway for inherited retinal diseases has highlighted the importance of achieving a molecular diagnosis for all new cases presenting to hospital eye services. The male germ cell-associated kinase ( MAK ) gene encodes a cilium-associated protein selectively expressed in the retina and testis, and has recently been implicated in autosomal recessive retinitis pigmentosa (RP). Whole exome sequencing has previously identified a homozygous Alu insertion in probands with recessive RP and nonsense and missense mutations have also been reported. Materials and methods Here we describe two novel mutations in different alleles of the MAK gene in a 75-year-old British female, who had a clinical diagnosis of RP () with onset in the fourth decade and no relevant family history. The mutations were established through next generation sequencing of a panel of 111 genes associated with RP and RP-like phenotypes. Results Two novel null mutations were identified within the MAK gene. The first c.1195_1196delAC p.(Thr399fs), was a two base-pair deletion creating a frame-shift in exon 9 predicted to result in nonsense-mediated decay. The second, c.279-2A>G, involved the splice acceptor consensus site upstream of exon 4, predicted to lead to aberrant splicing. Conclusions The natural history of this individual’s RP is consistent with previously described MAK mutations, being significantly milder than that associated with other photoreceptor ciliopathies. We suggest inclusion of MAK as part of wider genetic testing in all individuals presenting with RP. Click here to buy article

with mutations in PDE6A and PDE6B Samer Khateb, MD, PhD | Marco Nassisi, MD | Kinga M. Bujakowska, PhD | Cécile Méjécase, MSc | Christel Condroyer, MSc | Aline Antonio, BA | Marine Foussard, BA | Vanessa Démontant, BA | Saddek Mohand-Saïd, MD, PhD | José-Alain Sahel, MD | Christina Zeitz, PhD | Isabelle Audo, MD, PhD | JAMA Ophthalmol | 2019 Apr 18 | 137(6) | 669-679 | doi:10.1001/jamaophthalmol.2018.6367 Key Points Question What are the functional and structural changes over time of patients with rod-cone dystrophy harboring mutations in PDE6A and PDE6B? Findings In this cohort, longitudinal, follow-up study of 54 patients with rod-cone dystrophy and mutations in PDE6A or PDE6B, progressive photoreceptor degeneration was documented. The findings reveal a similar disease course between both genetic groups with preservation of functional visual abilities at older ages. Meaning The results of this study suggest that these functional and structural findings may enable a better prognostic estimation and candidate selection for photoreceptor therapeutic rescue. Abstract Importance A precise phenotypic characterization of retinal dystrophies is needed for disease modeling as a basis for future therapeutic interventions. Objective To compare genotype, phenotype, and structural changes in patients with rod-cone dystrophy (RCD) associated with mutations in PDE6A or PDE6B. To read more of the source article, click here.

Peng Yong Sim, V Swetha E Jeganathan, Alan F. Wright, Peter Cackett | 2018 Summary This case report depicts the clinical course of a female patient with unilateral retinitis pigmentosa, who first presented at the age of 12 years. Fundus photography at the time revealed unilateral pigmentary retinopathy, which was associated with extinguished electroretinogram (ERG) signal. At 35 years of age, fundus examination revealed deterioration of pre-existing unilateral pigmentary retinopathy with progressive visual field defect detected on Goldmann visual field testing. ERG findings remained unchanged and multifocal ERG showed unilateral decrease in amplitude in the affected eye. The patient was referred for genetic counselling. Next-generation sequencing identified a deleterious heterozygous c.118T>G (p.Cys40Gly) mutation in the CLRN1 gene. To read the full article, it must be purchased for $294. See link for details

"FDA Approves Gene Therapy for Inherited Blindness Developed by the University of Pennsylvania and Children’s Hospital of Philadelphia" | PennMedicine News Decision marks the first gene therapy approved for a genetic disease in the U.S. PHILADELPHIA – In a historic move, the U.S. Food and Drug Administration (FDA) today approved a gene therapy initially developed by researchers at the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) for the treatment of a rare, inherited form of retinal blindness. The decision marks the nation’s first gene therapy approved for the treatment of a genetic disease, and the first in which a new, corrective gene is injected directly into a patient. The therapy, known as LUXTURNA™ (voretigene neparvovec-ryzl), significantly improves eyesight in patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. Patients with RPE65 mutations suffer from severe visual impairment at infancy or early childhood, and by mid-life become totally blind. They previously had no pharmacologic treatment options. Spark Therapeutics, a Philadelphia biotechnology company created in 2013 by CHOP in an effort to accelerate the timeline for bringing new gene therapies to market, led the late-stage clinical development of LUXTURNA and built in West Philadelphia the first licensed manufacturing facility in the U.S. for a gene therapy treating an inherited disease. Spark was built on the foundational research conducted over a ten-year period by CHOP’s Center for Cellular and Molecular Therapeutics (CCMT). Those efforts were led by Jean Bennett, MD, PhD, the F.M. Kirby professor of Ophthalmology at the Perelman School of Medicine at the University of Pennsylvania and Penn’s Scheie Eye Institute, and Katherine A. High, MD, who directed the CCMT and now serves as Spark’s president and head of research and development. Albert M. Maguire, MD, a professor of Ophthalmology at the Perelman School of Medicine and an attending physician at CHOP, served as the principal investigator of the clinical trials which led to today’s FDA approval. Read entire press release

Tisiana Low, Anastassios Kostakis, Meena Balasubramanian |  Ophthalmic Genetics  | Nov 7 2017 | Vol 39, Issue 2 | pgs. 286-287 | doi/full/10.1080/13816810.2017.1393827 Introduction Retinitis pigmentosa (RP) refers to a group of inherited disorders that affect the retina’s ability to respond to light, leading to progressive visual loss. Retinitis pigmentosa sine pigmento is a variant of RP in which there is an absence of characteristic peripheral bone-spicule like pigmentary changes. One of the genes found to be responsible for RP is IFT140, a ciliary transporter gene (OMIM *614620). Homozygous and compound heterozygous IFT140 variants have commonly been reported in Mainzer-Saldino syndrome and Jeune syndrome(1). However, in recent literature, non-syndromic IFT140-related RP have been reported. IFT140 encodes a sub-unit of intraflagellar transport complex A (IFTA), which is involved in retrograde ciliary transport(2). It was previously referred to as KIAA0590 and located on chromosome 16p13.3. It is highly expressed in kidneys with moderate expression in ovary, testis, lung, prostate. Schmidts et al., 2013 demonstrated high expression of Ift140 in renal and retinal tissue in mouse embryos(3). Although the phenotype associated with IFT140 variants is still emerging, it appears to encompass a variable spectrum ranging from non-syndromic, isolated RP (as demonstrated in this clinical report) to Short-rib thoracic dysplasia 9 with or without polydactyly (SRTD9; OMIM # 266920). Case Report We present a case of a 22-year-old female who attended her opticians for a frequent headaches review. It was found that her visual fields were restricted, with a slightly abnormal retina with greying and mottling (Fig 1). However, night-time vision was not reduced. An optical coherence tomography suggested likely RP, and electrodiagnostic testing confirmed the diagnosis. She was the first child of healthy, non-consanguineous, White European parents and had a younger sister who was fit and well with no family history of RP. A recent ophthalmology follow-up review found that the patient had visual acuities of 6/6 with patchy visual defects in bilateral eyes, but no significant decrease in visual fields. Click here to purchase the article References Bifari IN, Elkhamary SM, Bolz HJ, et al. The ophthalmic phenotype of IFT140- related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy. Br J Ophthalmology. 2015; 0:1-5. Perrault I, Saunier S, Hanein S, et al. Mainzer-Saldino Syndrome Is a Ciliopathy Caused by IFT140 Mutations. Am J Hum Genet. 2012; 90(5):864–870. Schmidts M, Frank V, Eisenberger T, et al. Combined NGS Approaches Identify Mutations in the Intraflagellar Transport Gene IFT140 in Skeletal Ciliopathies with Early Progressive Kidney Disease. Hum Mutat. 2013; 34(5):714–724. Hull S, Owen N, Islam F, et al. Nonsyndromic retinal dystrophy due to bi-allelic mutations in the ciliary transport gene IFT140. Invest Ophthalmol Vis Sci. 2016; 57:1053–1062. Neveling K, Collin R, Gilissen C, et al. Next-generation genetic testing for retinitis pigmentosa. Hum Mutat. 2012; 33(6):963-972.