Evidence map›Paper›PMID 39191256›Full record

ArticleAmerican journal of human genetics2024

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

Samantha Malka, Pooja Biswas, Anne-Marie Berry, Riccardo Sangermano, Mukhtar Ullah, Siying Lin, Matteo D'Antonio, Aleksandr Jestin, Xiaodong Jiao, Mathieu Quinodoz and 36 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed.

  1. Review
  2. Article
  3. Ciliary Defects in Inherited Retinal Diseases.Advanced genetics (Hoboken, N.J.) · 2026
    Review
  4. Article
  5. Article
  6. Article
  7. Non-coding single-nucleotide and structural variants affecting the EYS putative promoter cause autosomal recessive retinitis pigmentosa.Genetics in medicine : official journal of the American College of Medical Genetics · 2025
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

46 authors.

Samantha MalkaMoorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK.
Pooja BiswasShiley Eye Institute, University of California, San Diego, San Diego, CA, USA.
Anne-Marie BerryShiley Eye Institute, University of California, San Diego, San Diego, CA, USA.
Riccardo SangermanoOcular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Mukhtar UllahInstitute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland.
Siying LinMoorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK.
Matteo D'AntonioDepartment of Medicine, Division of Biomedical Informatics, University of California, San Diego, La Jolla, CA, USA.
Aleksandr JestinUCL Institute of Ophthalmology, University College London, London, UK.
Xiaodong JiaoOphthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Mathieu QuinodozInstitute 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 SullivanHuman Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, TX, USA.
Jessica C GardnerUCL Institute of Ophthalmology, University College London, London, UK.
Emily M PlaceOcular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Michel MichaelidesMoorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK.
Karolina KaminskaInstitute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland.
Omar A MahrooMoorfields 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 SchiffMoorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK.
Genevieve WrightMoorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK.
Francesca CancellieriInstitute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland.
Veronika VaclavikHôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland.
Cristina SantosInstituto 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 RehmanDepartment of Zoology, Faculty of Biological and Health Sciences, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan.
Sudeep MehrotraOcular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Hafiz Muhammad Azhar BaigOcular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Muhammad IqbalDepartment of Biotechnology, Institute of Biochemistry, Biotechnology and Bioinformatics, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan.
Muhammad AnsarHôpital 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 SantosInstituto de Oftalmologia Dr. Gama Pinto (IOGP), Lisboa, Portugal.
Ana Berta SousaMedical 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 TranHôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland; Centre for Gene Therapy and Regenerative Medicine, King's College London, London, UK.
Hiroko MatsuiShiley Eye Institute, University of California, San Diego, San Diego, CA, USA.
Anjana BhatiaShiley Eye Institute, University of California, San Diego, San Diego, CA, USA.
Muhammad Asif NaeemNational Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
Shehla J AkramAkram Medical Complex, Lahore, Pakistan.
Javed AkramAllama Iqbal Medical Research Center, Lahore, Pakistan; Jinnah Burn and Reconstructive Surgery Center, Jinnah Hospital, Lahore, Pakistan.
Sheikh RiazuddinJinnah 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 AyusoDepartment 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 PierceOcular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Alison J HardcastleUCL Institute of Ophthalmology, University College London, London, UK.
S Amer RiazuddinThe Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Kelly A FrazerDepartment 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 HejtmancikOphthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Carlo RivoltaInstitute 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 BujakowskaOcular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Gavin ArnoMoorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK; Greenwood Genetic Center, Greenwood, SC, USA.
Andrew R WebsterMoorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK. Electronic address: andrew.webster@ucl.ac.uk.
Radha AyyagariShiley Eye Institute, University of California, San Diego, San Diego, CA, USA. Electronic address: rayyagari@health.ucsd.edu.

Funding

Statistical Methods for Gene Regulatory Analysis From Single Cell Genomics DataP20GM139769 · NIGMS · CLEMSON UNIVERSITY · PI ANHOLT, ROBERT R. H, ARNO, GAVIN · 2021 to 2025
$10.8M
Vision BiostatisticsP30EY022589 · NEI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Radha Ayyagari · 2012 to 2026
$10.3M
Molecular Basis of Hereditary Retinal DegenerationsR01EY021237 · NEI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI AYYAGARI, RADHA · 2011 to 2020
$5.6M
Molecular Mechanisms Underlying Macular DegenerationsR01EY013198 · NEI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI AYYAGARI, RADHA · 2001 to 2011
$4.0M
Unraveling the molecular pathology of retinal degeneration through single cell genomicsR01EY031663 · NEI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI AYYAGARI, RADHA, FRAZER, KELLY A · 2021 to 2025
$3.3M
Molecular mechanism underlying late-onset retinal/macular degenerationR01EY030591 · NEI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI AYYAGARI, RADHA · 2020 to 2023
$1.9M
NEI NIH HHS P30 EY022589NEI NIH HHS R01 EY013198NEI NIH HHS R01 EY021237NEI NIH HHS R01 EY030591NEI NIH HHS R01 EY031663NIGMS NIH HHS P20 GM139769Wellcome Trust 206619/Z/17/Z
6 · The paper itself

Abstract

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.

Indexed as

PedigreePolymorphism, Single NucleotideRetinitis PigmentosaAdultAllelesChildChild, PreschoolFemaleHaplotypesHeterozygoteHomozygoteHumansMaleMembrane ProteinsPhenotypeYoung AdultMembrane ProteinsTMEM216 protein, humanAfrican ancestryancestral alleleciliopathyequity of genetic testingethnic genetic diversitygene expressionnon-coding genetic variationretinal dystrophyretinitis pigmentosaSouth Asian

Identifiers

PMID39191256
PMCPMC11393691

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