Cargando…

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;...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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
_version_ 1784604682330570752
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
work_keys_str_mv AT manyisanoluthando amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT schrauwenisabelle amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT desouzariosleonardoalves amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT mowlashaheen amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT tekendongongangcedrik amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT popelkalinka amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT esohkevin amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT bharadwajthashi amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT nouelsaiedlizm amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT acharyaanushree amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT nasirabdul amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT wonkamtingangedmond amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT dekockcarmen amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT dandaracollet amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT lealsuzannem amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT wonkamambroise amonoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT manyisanoluthando monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT schrauwenisabelle monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT desouzariosleonardoalves monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT mowlashaheen monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT tekendongongangcedrik monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT popelkalinka monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT esohkevin monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT bharadwajthashi monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT nouelsaiedlizm monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT acharyaanushree monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT nasirabdul monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT wonkamtingangedmond monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT dekockcarmen monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT dandaracollet monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT lealsuzannem monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily
AT wonkamambroise monoallelicvariantinrestisassociatedwithnonsyndromicautosomaldominanthearingimpairmentinasouthafricanfamily