A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family

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dc.contributor.authorManyisa, Noluthando
dc.contributor.authorSchrauwen, Isabelle
dc.contributor.authorde Souza Rios, Leonardo Alves
dc.contributor.authorMowla, Shaheen
dc.contributor.authorTekendo-Ngongang, Cedrik
dc.contributor.authorPopel, Kalinka
dc.contributor.authorEsoh, Kevin
dc.contributor.authorBharadwaj, Thashi
dc.contributor.authorNouel-Saied, Liz M.
dc.contributor.authorAcharya, Anushree
dc.contributor.authorNasir, Abdul
dc.contributor.authorWonkam-Tingang, Edmond
dc.contributor.authorKock, Carmen de
dc.contributor.authorDandara, Collet
dc.contributor.authorLeal, Suzanne M.
dc.contributor.authorWonkam, Ambroise
dc.date.accessioned2021-11-29T14:58:20Z
dc.date.available2021-11-29T14:58:20Z
dc.date.issued2021-11-06
dc.date.updated2021-11-25T15:59:51Z
dc.description.abstractHearing 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.en_US
dc.identifierdoi: 10.3390/genes12111765
dc.identifier.apacitationManyisa, N., Schrauwen, I., de Souza Rios, L. A., Mowla, S., Tekendo-Ngongang, C., Popel, K., ... Wonkam, A. (2021). A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family. <i>Genes</i>, 12(11), 1765. http://hdl.handle.net/11427/35396en_ZA
dc.identifier.chicagocitationManyisa, Noluthando, Isabelle Schrauwen, Leonardo Alves de Souza Rios, Shaheen Mowla, Cedrik Tekendo-Ngongang, Kalinka Popel, Kevin Esoh, et al "A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family." <i>Genes</i> 12, 11. (2021): 1765. http://hdl.handle.net/11427/35396en_ZA
dc.identifier.citationManyisa, N., Schrauwen, I., de Souza Rios, L.A., Mowla, S., Tekendo-Ngongang, C., Popel, K., Esoh, K. & Bharadwaj, T. et al. 2021. A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family. <i>Genes.</i> 12(11):1765. http://hdl.handle.net/11427/35396en_ZA
dc.identifier.ris TY - Journal Article AU - Manyisa, Noluthando AU - Schrauwen, Isabelle AU - de Souza Rios, Leonardo Alves AU - Mowla, Shaheen AU - Tekendo-Ngongang, Cedrik AU - Popel, Kalinka AU - Esoh, Kevin AU - Bharadwaj, Thashi AU - Nouel-Saied, Liz M. AU - Acharya, Anushree AU - Nasir, Abdul AU - Wonkam-Tingang, Edmond AU - Kock, Carmen de AU - Dandara, Collet AU - Leal, Suzanne M. AU - Wonkam, Ambroise AB - 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. DA - 2021-11-06 DB - OpenUCT DP - University of Cape Town IS - 11 J1 - Genes LK - https://open.uct.ac.za PY - 2021 T1 - A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family TI - A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family UR - http://hdl.handle.net/11427/35396 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/35396
dc.identifier.vancouvercitationManyisa N, Schrauwen I, de Souza Rios LA, Mowla S, Tekendo-Ngongang C, Popel K, et al. A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family. Genes. 2021;12(11):1765. http://hdl.handle.net/11427/35396.en_ZA
dc.language.isoenen_US
dc.publisher.departmentDepartment of Medicineen_US
dc.publisher.facultyFaculty of Health Sciencesen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourceGenesen_US
dc.source.journalissue11en_US
dc.source.journalvolume12en_US
dc.source.pagination1765en_US
dc.source.urihttps://www.mdpi.com/journal/genes
dc.titleA Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Familyen_US
dc.typeJournal Articleen_US
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