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

2024-09-05Artigo científico Acesso aberto
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dc.contributor.authorMalka, Samantha
dc.contributor.authorBiswas, Pooja
dc.contributor.authorBerry, Anne Marie
dc.contributor.authorSangermano, Riccardo
dc.contributor.authorUllah, Mukhtar
dc.contributor.authorLin, Siying
dc.contributor.authorD'Antonio, Matteo
dc.contributor.authorJestin, Aleksandr
dc.contributor.authorJiao, Xiaodong
dc.contributor.authorQuinodoz, Mathieu
dc.contributor.authorSullivan, Lori
dc.contributor.authorGardner, Jessica C.
dc.contributor.authorPlace, Emily M.
dc.contributor.authorMichaelides, Michel
dc.contributor.authorKaminska, Karolina
dc.contributor.authorMahroo, Omar A.
dc.contributor.authorSchiff, Elena
dc.contributor.authorWright, Genevieve
dc.contributor.authorCancellieri, Francesca
dc.contributor.authorVaclavik, Veronika
dc.contributor.authorSantos, Cristina
dc.contributor.authorRehman, Atta Ur
dc.contributor.authorMehrotra, Sudeep
dc.contributor.authorAzhar Baig, Hafiz Muhammad
dc.contributor.authorIqbal, Muhammad
dc.contributor.authorAnsar, Muhammad
dc.contributor.authorSantos, Luisa Coutinho
dc.contributor.authorSousa, Ana Berta
dc.contributor.authorTran, Viet H.
dc.contributor.authorMatsui, Hiroko
dc.contributor.authorBhatia, Anjana
dc.contributor.authorNaeem, Muhammad Asif
dc.contributor.authorAkram, Shehla J.
dc.contributor.authorAkram, Javed
dc.contributor.authorRiazuddin, Sheikh
dc.contributor.authorAyuso, Carmen
dc.contributor.authorPierce, Eric A.
dc.contributor.authorHardcastle, Alison J.
dc.contributor.authorRiazuddin, S. Amer
dc.contributor.authorFrazer, Kelly A.
dc.contributor.authorHejtmancik, J. Fielding
dc.contributor.authorRivolta, Carlo
dc.contributor.authorBujakowska, Kinga M.
dc.contributor.authorArno, Gavin
dc.contributor.authorWebster, Andrew R.
dc.contributor.authorAyyagari, Radha
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.pblCell Press
dc.date.accessioned2024-09-30T22:28:48Z
dc.date.available2024-09-30T22:28:48Z
dc.date.issued2024-09-05
dc.descriptionPublisher Copyright: Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.
dc.description.abstractGenome 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.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent19
dc.format.extent4043417
dc.identifier.doi10.1016/j.ajhg.2024.07.020
dc.identifier.issn1537-6605
dc.identifier.otherPURE: 99518474
dc.identifier.otherPURE UUID: 2abcf76f-b3cd-4794-8c97-12cd9c8ee1fd
dc.identifier.otherScopus: 85203475022
dc.identifier.otherPubMed: 39191256
dc.identifier.urihttp://hdl.handle.net/10362/172704
dc.identifier.urlhttps://www.scopus.com/pages/publications/85203475022
dc.language.isoeng
dc.peerreviewedyes
dc.subjectAfrican ancestry
dc.subjectancestral allele
dc.subjectciliopathy
dc.subjectequity of genetic testing
dc.subjectethnic genetic diversity
dc.subjectgene expression
dc.subjectnon-coding genetic variation
dc.subjectretinal dystrophy
dc.subjectretinitis pigmentosa
dc.subjectSouth Asian
dc.subjectGenetics
dc.subjectGenetics(clinical)
dc.titleSubstitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expressionen
dc.typejournal article
degois.publication.firstPage2012
degois.publication.issue9
degois.publication.lastPage2030
degois.publication.titleAmerican journal of human genetics
degois.publication.volume111
dspace.entity.typePublication
rcaap.rightsopenAccess

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