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

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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
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2024-08-26 , DOI: 10.1016/j.ajhg.2024.07.020
Samantha Malka ₁ , Pooja Biswas ₂ , Anne-Marie Berry ₂ , Riccardo Sangermano ₃ , Mukhtar Ullah ₄ , Siying Lin ₁ , Matteo D'Antonio ₅ , Aleksandr Jestin ₆ , Xiaodong Jiao ₇ , Mathieu Quinodoz ₈ , Lori Sullivan ₉ , Jessica C Gardner ₆ , Emily M Place ₃ , Michel Michaelides ₁ , Karolina Kaminska ₄ , Omar A Mahroo ₁₀ , Elena Schiff ₁ , Genevieve Wright ₁ , Francesca Cancellieri ₄ , Veronika Vaclavik ₁₁ , Cristina Santos ₁₂ , Atta Ur Rehman ₁₃ , Sudeep Mehrotra ₃ , Hafiz Muhammad Azhar Baig ₃ , Muhammad Iqbal ₁₄ , Muhammad Ansar ₁₅ , Luisa Coutinho Santos ₁₆ , Ana Berta Sousa ₁₇ , Viet H Tran ₁₈ , Hiroko Matsui ₂ , Anjana Bhatia ₂ , Muhammad Asif Naeem ₁₉ , Shehla J Akram ₂₀ , Javed Akram ₂₁ , Sheikh Riazuddin ₂₂ , Carmen Ayuso ₂₃ , Eric A Pierce ₃ , Alison J Hardcastle ₆ , S Amer Riazuddin ₂₄ , Kelly A Frazer ₂₅ , J Fielding Hejtmancik ₇ , Carlo Rivolta ₈ , Kinga M Bujakowska ₃ , Gavin Arno ₂₆ , Andrew R Webster ₁ , Radha Ayyagari ₂

Affiliation

Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK.
Shiley Eye Institute, University of California, San Diego, San Diego, CA, USA.
Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland.
Department of Medicine, Division of Biomedical Informatics, University of California, San Diego, La Jolla, CA, USA.
UCL Institute of Ophthalmology, University College London, London, UK.
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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.
Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, TX, USA.
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.
Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland.
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.
Department of Zoology, Faculty of Biological and Health Sciences, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan.
Department of Biotechnology, Institute of Biochemistry, Biotechnology and Bioinformatics, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan.
Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland; Advanced Molecular Genetics and Genomics Disease Research and Treatment Centre, Dow University of Health Sciences, Karachi 74200, Pakistan.
Instituto de Oftalmologia Dr. Gama Pinto (IOGP), Lisboa, Portugal.
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.
Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland; Centre for Gene Therapy and Regenerative Medicine, King's College London, London, UK.
National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
Akram Medical Complex, Lahore, Pakistan.
Allama Iqbal Medical Research Center, Lahore, Pakistan; Jinnah Burn and Reconstructive Surgery Center, Jinnah Hospital, Lahore, Pakistan.
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.
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.
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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.
Moorfields Eye Hospital NHS Trust, London, UK; UCL Institute of Ophthalmology, University College London, London, UK; Greenwood Genetic Center, Greenwood, SC, USA.

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.

中文翻译：

TMEM216上游单个非编码核苷酸的取代会导致非综合征性视网膜色素变性，并与 TMEM216 表达降低有关

对受视网膜色素变性（RP）影响的个体的基因组分析在 11 号染色体（g.61392563 [GRCh38]）的同一基因组位置发现了两个罕见的核苷酸替换，纤毛病基因 TMEM216 （c.−69G>A， c.−69G>T [GenBank： NM_001173991.3]）起始密码子上游的 69 个碱基对，分别在南亚和非洲血统的个体中。基因型包括 71 个纯合子和 3 个混合杂合子，具有预测的功能丧失等位基因。单倍型分析显示单核苷酸变异（SNV）在家庭中很常见，表明祖先等位基因位于两个不同的种族群体中。对来自 49 个家庭的 62 名可用个体的临床表型分析表明，临床表现相似，前 10 年出现夜盲症，此后进行性外周视野丧失。未发现明显的全身性纤毛病特征。通过荧光素酶报告基因测定对这些变体的功能表征显示启动子活性降低。纳米孔测序证实，来自杂合载体的血液来源的 RNA 中 c.-69G>T 等位基因的 TMEM216 c.-69G>T 等位基因的转录较低，并通过 qPCR 进一步概括了表达降低，使用白细胞来源的 c.-69G>T 纯合子 RNA 和来自携带纯合子 c.-69G>A 的基因组编辑 hTERT-RPE1 细胞的总 RNA-TMEM216。总之，这些变异解释了很大一部分未解决的病例，特别是在非洲血统的个体中，表明TMEM216表达降低可能导致纤毛发生异常和光感受器变性。

更新日期：2024-08-26

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