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

African ancestry South Asian ancestral allele ciliopathy equity of genetic testing ethnic genetic diversity gene expression non-coding genetic variation retinal dystrophy retinitis pigmentosa

Journal

American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475

Informations de publication

Date de publication:
20 Aug 2024
Historique:
received: 29 03 2024
revised: 26 07 2024
accepted: 29 07 2024
medline: 28 8 2024
pubmed: 28 8 2024
entrez: 27 8 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.ajhg.2024.07.020 PMID: 39191256
pubmed: 39191256
pii: S0002-9297(24)00281-7
doi: 10.1016/j.ajhg.2024.07.020
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests All the authors declare no competing interests.

Auteurs

Samantha Malka (S)

Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK.

Pooja Biswas (P)

Shiley Eye Institute, University of California, San Diego, San Diego, CA, USA.

Anne-Marie Berry (AM)

Shiley Eye Institute, University of California, San Diego, San Diego, CA, USA.

Riccardo Sangermano (R)

Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Mukhtar Ullah (M)

Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland.

Siying Lin (S)

Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK.

Matteo D'Antonio (M)

Department of Medicine, Division of Biomedical Informatics, University of California, San Diego, La Jolla, CA, USA.

Aleksandr Jestin (A)

UCL Institute of Ophthalmology, University College London, London, UK.

Xiaodong Jiao (X)

Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Mathieu 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.

Lori Sullivan (L)

Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, TX, USA.

Jessica C Gardner (JC)

UCL Institute of Ophthalmology, University College London, London, UK.

Emily M Place (EM)

Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Michel Michaelides (M)

Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK.

Karolina Kaminska (K)

Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland.

Omar A 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.

Elena Schiff (E)

Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK.

Genevieve Wright (G)

Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK.

Francesca Cancellieri (F)

Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland.

Veronika Vaclavik (V)

Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland.

Cristina 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.

Atta Ur Rehman (AU)

Department of Zoology, Faculty of Biological and Health Sciences, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan.

Sudeep Mehrotra (S)

Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Hafiz Muhammad Azhar Baig (HM)

Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Muhammad Iqbal (M)

Department of Biotechnology, Institute of Biochemistry, Biotechnology and Bioinformatics, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan.

Muhammad 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.

Luisa Coutinho Santos (LC)

Instituto de Oftalmologia Dr. Gama Pinto (IOGP), Lisboa, Portugal.

Ana Berta 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.

Viet H Tran (VH)

Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland; Centre for Gene Therapy and Regenerative Medicine, King's College London, London, UK.

Hiroko Matsui (H)

Shiley Eye Institute, University of California, San Diego, San Diego, CA, USA.

Anjana Bhatia (A)

Shiley Eye Institute, University of California, San Diego, San Diego, CA, USA.

Muhammad Asif Naeem (MA)

National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.

Shehla J Akram (SJ)

Akram Medical Complex, Lahore, Pakistan.

Javed Akram (J)

Allama Iqbal Medical Research Center, Lahore, Pakistan; Jinnah Burn and Reconstructive Surgery Center, Jinnah Hospital, Lahore, Pakistan.

Sheikh 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.

Carmen 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.

Eric A Pierce (EA)

Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Alison J Hardcastle (AJ)

UCL Institute of Ophthalmology, University College London, London, UK.

S Amer Riazuddin (SA)

The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Kelly A 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.

J Fielding Hejtmancik (JF)

Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Carlo 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.

Kinga M Bujakowska (KM)

Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Gavin Arno (G)

Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK; Greenwood Genetic Center, Greenwood, SC, USA.

Andrew R 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.

Radha Ayyagari (R)

Shiley Eye Institute, University of California, San Diego, San Diego, CA, USA. Electronic address: rayyagari@health.ucsd.edu.

Classifications MeSH