Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression.

Autor:	Malka S; Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK., Biswas P; Shiley Eye Institute, University of California, San Diego, San Diego, CA, USA., Berry AM; Shiley Eye Institute, University of California, San Diego, San Diego, CA, USA., Sangermano R; Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA., Ullah M; Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland., Lin S; Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK., D'Antonio M; Department of Medicine, Division of Biomedical Informatics, University of California, San Diego, La Jolla, CA, USA., Jestin A; UCL Institute of Ophthalmology, University College London, London, UK., Jiao X; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA., Quinodoz M; Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Sullivan L; Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, TX, USA., Gardner JC; UCL Institute of Ophthalmology, University College London, London, UK., Place EM; Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA., Michaelides M; Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK., Kaminska K; Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland., Mahroo OA; Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK; Department of Ophthalmology, St Thomas' Hospital, London, UK; Section of Ophthalmology, King's College London, St Thomas' Hospital Campus, London, UK., Schiff E; Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK., Wright G; Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK., Cancellieri F; Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland., Vaclavik V; Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland., Santos C; Instituto de Oftalmologia Dr. Gama Pinto (IOGP), Lisboa, Portugal; Faculdade de Ciências Médicas, NMS, FCM, NOVA Medical School, Universidade NOVA de Lisboa, 7 iNOVA4Health, Lisboa, Portugal., Rehman AU; Department of Zoology, Faculty of Biological and Health Sciences, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan., Mehrotra S; Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA., Azhar Baig HM; Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA., Iqbal M; Department of Biotechnology, Institute of Biochemistry, Biotechnology and Bioinformatics, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan., Ansar M; Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland; Advanced Molecular Genetics and Genomics Disease Research and Treatment Centre, Dow University of Health Sciences, Karachi 74200, Pakistan., Santos LC; Instituto de Oftalmologia Dr. Gama Pinto (IOGP), Lisboa, Portugal., Sousa AB; Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Lisboa Norte (CHULN), Lisboa, Portugal; Serviço de Genética Médica, Departamento de Pediatria, Hospital de Santa Maria, Lisboa, Portugal., Tran VH; Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland; Centre for Gene Therapy and Regenerative Medicine, King's College London, London, UK., Matsui H; Shiley Eye Institute, University of California, San Diego, San Diego, CA, USA., Bhatia A; Shiley Eye Institute, University of California, San Diego, San Diego, CA, USA., Naeem MA; National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan., Akram SJ; Akram Medical Complex, Lahore, Pakistan., Akram J; Allama Iqbal Medical Research Center, Lahore, Pakistan; Jinnah Burn and Reconstructive Surgery Center, Jinnah Hospital, Lahore, Pakistan., Riazuddin S; Jinnah Burn and Reconstructive Surgery Center, Jinnah Hospital, Lahore, Pakistan; Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28049 Madrid, Spain., Ayuso C; Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28049 Madrid, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain., Pierce EA; Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA., Hardcastle AJ; UCL Institute of Ophthalmology, University College London, London, UK., Riazuddin SA; The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Frazer KA; Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA, USA., Hejtmancik JF; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA., Rivolta C; Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Bujakowska KM; Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA., Arno G; Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK; Greenwood Genetic Center, Greenwood, SC, USA., Webster AR; Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK. Electronic address: andrew.webster@ucl.ac.uk., Ayyagari R; Shiley Eye Institute, University of California, San Diego, San Diego, CA, USA. Electronic address: rayyagari@health.ucsd.edu.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2024 Sep 05; Vol. 111 (9), pp. 2012-2030. Date of Electronic Publication: 2024 Aug 26.
DOI:	10.1016/j.ajhg.2024.07.020
Abstrakt:	Genome analysis of individuals affected by retinitis pigmentosa (RP) identified two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]), in individuals of South Asian and African ancestry, respectively. Genotypes included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations. Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted. Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity. Nanopore sequencing confirmed the lower transcription of the TMEM216 c.-69G>T allele in blood-derived RNA from a heterozygous carrier, and reduced expression was further recapitulated by qPCR, using both leukocytes-derived RNA of c.-69G>T homozygotes and total RNA from genome-edited hTERT-RPE1 cells carrying homozygous TMEM216 c.-69G>A. In conclusion, these variants explain a significant proportion of unsolved cases, specifically in individuals of African ancestry, suggesting that reduced TMEM216 expression might lead to abnormal ciliogenesis and photoreceptor degeneration. Competing Interests: Declaration of interests All the authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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