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A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family
Hearing impairment (HI) is a sensory disorder with a prevalence of 0.0055 live births in South Africa. DNA samples from a South African family presenting with progressive, autosomal dominant non-syndromic HI were subjected to whole-exome sequencing, and a novel monoallelic variant in REST [c.1244GC;...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618167/ https://www.ncbi.nlm.nih.gov/pubmed/34828371 http://dx.doi.org/10.3390/genes12111765 |
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author | Manyisa, Noluthando Schrauwen, Isabelle de Souza Rios, Leonardo Alves Mowla, Shaheen Tekendo-Ngongang, Cedrik Popel, Kalinka Esoh, Kevin Bharadwaj, Thashi Nouel-Saied, Liz M. Acharya, Anushree Nasir, Abdul Wonkam-Tingang, Edmond de Kock, Carmen Dandara, Collet Leal, Suzanne M. Wonkam, Ambroise |
author_facet | Manyisa, Noluthando Schrauwen, Isabelle de Souza Rios, Leonardo Alves Mowla, Shaheen Tekendo-Ngongang, Cedrik Popel, Kalinka Esoh, Kevin Bharadwaj, Thashi Nouel-Saied, Liz M. Acharya, Anushree Nasir, Abdul Wonkam-Tingang, Edmond de Kock, Carmen Dandara, Collet Leal, Suzanne M. Wonkam, Ambroise |
author_sort | Manyisa, Noluthando |
collection | PubMed |
description | Hearing impairment (HI) is a sensory disorder with a prevalence of 0.0055 live births in South Africa. DNA samples from a South African family presenting with progressive, autosomal dominant non-syndromic HI were subjected to whole-exome sequencing, and a novel monoallelic variant in REST [c.1244GC; p.(C415S)], was identified as the putative causative variant. The co-segregation of the variant was confirmed with Sanger Sequencing. The variant is absent from databases, 103 healthy South African controls, and 52 South African probands with isolated HI. In silico analysis indicates that the p.C415S variant in REST substitutes a conserved cysteine and results in changes to the surrounding secondary structure and the disulphide bonds, culminating in alteration of the tertiary structure of REST. Localization studies using ectopically expressed GFP-tagged Wild type (WT) and mutant REST in HEK-293 cells show that WT REST localizes exclusively to the nucleus; however, the mutant protein localizes throughout the cell. Additionally, mutant REST has an impaired ability to repress its known target AF1q. The data demonstrates that the identified mutation compromises the function of REST and support its implication in HI. This study is the second report, worldwide, to implicate REST in HI and suggests that it should be included in diagnostic HI panels. |
format | Online Article Text |
id | pubmed-8618167 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-86181672021-11-27 A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family Manyisa, Noluthando Schrauwen, Isabelle de Souza Rios, Leonardo Alves Mowla, Shaheen Tekendo-Ngongang, Cedrik Popel, Kalinka Esoh, Kevin Bharadwaj, Thashi Nouel-Saied, Liz M. Acharya, Anushree Nasir, Abdul Wonkam-Tingang, Edmond de Kock, Carmen Dandara, Collet Leal, Suzanne M. Wonkam, Ambroise Genes (Basel) Article Hearing impairment (HI) is a sensory disorder with a prevalence of 0.0055 live births in South Africa. DNA samples from a South African family presenting with progressive, autosomal dominant non-syndromic HI were subjected to whole-exome sequencing, and a novel monoallelic variant in REST [c.1244GC; p.(C415S)], was identified as the putative causative variant. The co-segregation of the variant was confirmed with Sanger Sequencing. The variant is absent from databases, 103 healthy South African controls, and 52 South African probands with isolated HI. In silico analysis indicates that the p.C415S variant in REST substitutes a conserved cysteine and results in changes to the surrounding secondary structure and the disulphide bonds, culminating in alteration of the tertiary structure of REST. Localization studies using ectopically expressed GFP-tagged Wild type (WT) and mutant REST in HEK-293 cells show that WT REST localizes exclusively to the nucleus; however, the mutant protein localizes throughout the cell. Additionally, mutant REST has an impaired ability to repress its known target AF1q. The data demonstrates that the identified mutation compromises the function of REST and support its implication in HI. This study is the second report, worldwide, to implicate REST in HI and suggests that it should be included in diagnostic HI panels. MDPI 2021-11-06 /pmc/articles/PMC8618167/ /pubmed/34828371 http://dx.doi.org/10.3390/genes12111765 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Manyisa, Noluthando Schrauwen, Isabelle de Souza Rios, Leonardo Alves Mowla, Shaheen Tekendo-Ngongang, Cedrik Popel, Kalinka Esoh, Kevin Bharadwaj, Thashi Nouel-Saied, Liz M. Acharya, Anushree Nasir, Abdul Wonkam-Tingang, Edmond de Kock, Carmen Dandara, Collet Leal, Suzanne M. Wonkam, Ambroise A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family |
title | A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family |
title_full | A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family |
title_fullStr | A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family |
title_full_unstemmed | A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family |
title_short | A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family |
title_sort | monoallelic variant in rest is associated with non-syndromic autosomal dominant hearing impairment in a south african family |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618167/ https://www.ncbi.nlm.nih.gov/pubmed/34828371 http://dx.doi.org/10.3390/genes12111765 |
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