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

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.

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Publication Details

Journal
The American Journal of Human Genetics
Published
2024-08-26
DOI
https://doi.org/10.1016/j.ajhg.2024.07.020
Citations
6
Primary Topic
Retinal Development and Disorders
Type
article
Field-Weighted Citation Impact
1.40

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article

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

Kinga M. Bujakowska, Riccardo Sangermano, Hoai Viet Tran, Carlo Rivolta et al.
6 citations
The American Journal of Human Genetics
Retinal Development and Disorders
1.40
article

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

Kinga M. Bujakowska, Riccardo Sangermano, Hoai Viet Tran, Carlo Rivolta, Jessica C. Gardner, Samantha Malka, Ana Berta Sousa, Siying Lin, Atta Ur Rehman, Javed Akram, Hafiz Muhammad Azhar Baig, Luísa Coutinho Santos, Pooja Biswas, Karolina Kamińska, Cristina Santos, Eric A. Pierce, Matteo D’Antonio, Elena Schiff, Anjana Bhatia, Carmen Ayuso, Omar A. Mahroo, Alison J. Hardcastle, Mathieu Quinodoz, Muhammad Ansar, Francesca Cancellieri, Michel Michaelides, Gavin Arno, Emily Place, Radha Ayyagari, Veronika Vaclavik, Kelly A. Frazer, Muhammad Asif Naeem, Andrew R. Webster, Shehla Javed Akram, J. Fielding Hejtmancik, Mukhtar Ullah, Muhammad Iqbal, Sudeep Mehrotra, Sheikh Riazuddin, Xiaodong Jiao, Anne-Marie Berry, Lori S. Sullivan, Hiroko Matsui, A. Jestin, Genevieve Wright
article en
6 citations

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.

The American Journal of Human GeneticsVol. 111(9)
Massachusetts Eye and Ear Infirmary (US), National Institutes of Health (US), Jinnah Postgraduate Medical Center (PK), St Thomas' Hospital (GB), Moorfields Eye Hospital NHS Foundation Trust (GB), Harvard University (US), Johns Hopkins University (US), University of Leicester (GB), University of the Punjab (PK), Islamia University of Bahawalpur (PK), King's College London (GB), University of Basel (CH), Allama Iqbal Medical College (PK), Hazara University (PK), Johns Hopkins Medicine (US), UC San Diego Health System (US), Instituto de Salud Carlos III (ES), University of California San Diego (US), Dow University of Health Sciences (PK), Hôpital Ophtalmique Jules-Gonin (CH), Cell and Gene Therapy Catapult (GB), Centre for Biomedical Network Research on Rare Diseases (ES), Centro Hospitalar Lisboa Norte (PT), Hospital Universitario Fundación Jiménez Díaz (ES), National Eye Institute (US), Centre of Excellence in Molecular Biology (PK), Greenwood Genetic Center (US), Hospital de Santa Maria (PT), Moorfields Eye Hospital (GB), Institute of Molecular and Clinical Ophthalmology Basel (CH), University College London (GB), Smith-Kettlewell Eye Research Institute (US), Universidad Autónoma de Madrid (ES), Universidade Nova de Lisboa (PT), The University of Texas Health Science Center at Houston (US)
Foundation Fighting Blindness, Research to Prevent Blindness, Fight for Sight UK, National Institutes of Health, NHLBI Division of Intramural Research
Zero hunger
Openalex Percentile: Top 19%
Retinal Development and Disorders
1.40
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