A Monoallelic Variant in <i>REST</i> 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 <i>REST&l...

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Autores principales:	Noluthando Manyisa, Isabelle Schrauwen, Leonardo Alves de Souza Rios, Shaheen Mowla, Cedrik Tekendo-Ngongang, Kalinka Popel, Kevin Esoh, Thashi Bharadwaj, Liz M. Nouel-Saied, Anushree Acharya, Abdul Nasir, Edmond Wonkam-Tingang, Carmen de Kock, Collet Dandara, Suzanne M. Leal, Ambroise Wonkam
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	<i>REST</i> RE1-silencing transcription factor non-syndromic hearing impairment South Africa Africa <i>DFNA27</i> Genetics QH426-470
Acceso en línea:	https://doaj.org/article/c996db29cf5246ba9d5c149767b6aa66
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spelling	oai:doaj.org-article:c996db29cf5246ba9d5c149767b6aa662021-11-25T17:41:40ZA Monoallelic Variant in <i>REST</i> Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family10.3390/genes121117652073-4425https://doaj.org/article/c996db29cf5246ba9d5c149767b6aa662021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4425/12/11/1765https://doaj.org/toc/2073-4425Hearing 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 <i>REST</i> [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 <i>REST</i> 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 <i>REST</i> 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 <i>AF1q</i>. The data demonstrates that the identified mutation compromises the function of <i>REST</i> and support its implication in HI. This study is the second report, worldwide, to implicate <i>REST</i> in HI and suggests that it should be included in diagnostic HI panels.Noluthando ManyisaIsabelle SchrauwenLeonardo Alves de Souza RiosShaheen MowlaCedrik Tekendo-NgongangKalinka PopelKevin EsohThashi BharadwajLiz M. Nouel-SaiedAnushree AcharyaAbdul NasirEdmond Wonkam-TingangCarmen de KockCollet DandaraSuzanne M. LealAmbroise WonkamMDPI AGarticle<i>REST</i>RE1-silencing transcription factornon-syndromic hearing impairmentSouth AfricaAfrica<i>DFNA27</i>GeneticsQH426-470ENGenes, Vol 12, Iss 1765, p 1765 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	<i>REST</i> RE1-silencing transcription factor non-syndromic hearing impairment South Africa Africa <i>DFNA27</i> Genetics QH426-470
spellingShingle	<i>REST</i> RE1-silencing transcription factor non-syndromic hearing impairment South Africa Africa <i>DFNA27</i> Genetics QH426-470 Noluthando Manyisa Isabelle Schrauwen Leonardo Alves de Souza Rios Shaheen Mowla Cedrik Tekendo-Ngongang Kalinka Popel Kevin Esoh Thashi Bharadwaj Liz M. Nouel-Saied Anushree Acharya Abdul Nasir Edmond Wonkam-Tingang Carmen de Kock Collet Dandara Suzanne M. Leal Ambroise Wonkam A Monoallelic Variant in <i>REST</i> Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family
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 <i>REST</i> [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 <i>REST</i> 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 <i>REST</i> 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 <i>AF1q</i>. The data demonstrates that the identified mutation compromises the function of <i>REST</i> and support its implication in HI. This study is the second report, worldwide, to implicate <i>REST</i> in HI and suggests that it should be included in diagnostic HI panels.
format	article
author	Noluthando Manyisa Isabelle Schrauwen Leonardo Alves de Souza Rios Shaheen Mowla Cedrik Tekendo-Ngongang Kalinka Popel Kevin Esoh Thashi Bharadwaj Liz M. Nouel-Saied Anushree Acharya Abdul Nasir Edmond Wonkam-Tingang Carmen de Kock Collet Dandara Suzanne M. Leal Ambroise Wonkam
author_facet	Noluthando Manyisa Isabelle Schrauwen Leonardo Alves de Souza Rios Shaheen Mowla Cedrik Tekendo-Ngongang Kalinka Popel Kevin Esoh Thashi Bharadwaj Liz M. Nouel-Saied Anushree Acharya Abdul Nasir Edmond Wonkam-Tingang Carmen de Kock Collet Dandara Suzanne M. Leal Ambroise Wonkam
author_sort	Noluthando Manyisa
title	A Monoallelic Variant in <i>REST</i> Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family
title_short	A Monoallelic Variant in <i>REST</i> Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family
title_full	A Monoallelic Variant in <i>REST</i> Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family
title_fullStr	A Monoallelic Variant in <i>REST</i> Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family
title_full_unstemmed	A Monoallelic Variant in <i>REST</i> Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family
title_sort	monoallelic variant in <i>rest</i> is associated with non-syndromic autosomal dominant hearing impairment in a south african family
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/c996db29cf5246ba9d5c149767b6aa66
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A Monoallelic Variant in <i>REST</i> Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family

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