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Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients

CDC14A encodes the Cell Division Cycle 14A protein and has been associated with autosomal recessive non-syndromic hearing loss (DFNB32), as well as hearing impairment and infertile male syndrome (HIIMS) since 2016. To date, only nine variants have been associated in patients whose initial symptoms i...

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Autores principales: Doll, Julia, Kolb, Susanne, Schnapp, Linda, Rad, Aboulfazl, Rüschendorf, Franz, Khan, Imran, Adli, Abolfazl, Hasanzadeh, Atefeh, Liedtke, Daniel, Knaup, Sabine, Hofrichter, Michaela AH, Müller, Tobias, Dittrich, Marcus, Kong, Il-Keun, Kim, Hyung-Goo, Haaf, Thomas, Vona, Barbara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982189/
https://www.ncbi.nlm.nih.gov/pubmed/31906439
http://dx.doi.org/10.3390/ijms21010311
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author Doll, Julia
Kolb, Susanne
Schnapp, Linda
Rad, Aboulfazl
Rüschendorf, Franz
Khan, Imran
Adli, Abolfazl
Hasanzadeh, Atefeh
Liedtke, Daniel
Knaup, Sabine
Hofrichter, Michaela AH
Müller, Tobias
Dittrich, Marcus
Kong, Il-Keun
Kim, Hyung-Goo
Haaf, Thomas
Vona, Barbara
author_facet Doll, Julia
Kolb, Susanne
Schnapp, Linda
Rad, Aboulfazl
Rüschendorf, Franz
Khan, Imran
Adli, Abolfazl
Hasanzadeh, Atefeh
Liedtke, Daniel
Knaup, Sabine
Hofrichter, Michaela AH
Müller, Tobias
Dittrich, Marcus
Kong, Il-Keun
Kim, Hyung-Goo
Haaf, Thomas
Vona, Barbara
author_sort Doll, Julia
collection PubMed
description CDC14A encodes the Cell Division Cycle 14A protein and has been associated with autosomal recessive non-syndromic hearing loss (DFNB32), as well as hearing impairment and infertile male syndrome (HIIMS) since 2016. To date, only nine variants have been associated in patients whose initial symptoms included moderate-to-profound hearing impairment. Exome analysis of Iranian and Pakistani probands who both showed bilateral, sensorineural hearing loss revealed a novel splice site variant (c.1421+2T>C, p.?) that disrupts the splice donor site and a novel frameshift variant (c.1041dup, p.Ser348Glnfs*2) in the gene CDC14A, respectively. To evaluate the pathogenicity of both loss-of-function variants, we analyzed the effects of both variants on the RNA-level. The splice variant was characterized using a minigene assay. Altered expression levels due to the c.1041dup variant were assessed using RT-qPCR. In summary, cDNA analysis confirmed that the c.1421+2T>C variant activates a cryptic splice site, resulting in a truncated transcript (c.1414_1421del, p.Val472Leufs*20) and the c.1041dup variant results in a defective transcript that is likely degraded by nonsense-mediated mRNA decay. The present study functionally characterizes two variants and provides further confirmatory evidence that CDC14A is associated with a rare form of hereditary hearing loss.
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spelling pubmed-69821892020-02-07 Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients Doll, Julia Kolb, Susanne Schnapp, Linda Rad, Aboulfazl Rüschendorf, Franz Khan, Imran Adli, Abolfazl Hasanzadeh, Atefeh Liedtke, Daniel Knaup, Sabine Hofrichter, Michaela AH Müller, Tobias Dittrich, Marcus Kong, Il-Keun Kim, Hyung-Goo Haaf, Thomas Vona, Barbara Int J Mol Sci Article CDC14A encodes the Cell Division Cycle 14A protein and has been associated with autosomal recessive non-syndromic hearing loss (DFNB32), as well as hearing impairment and infertile male syndrome (HIIMS) since 2016. To date, only nine variants have been associated in patients whose initial symptoms included moderate-to-profound hearing impairment. Exome analysis of Iranian and Pakistani probands who both showed bilateral, sensorineural hearing loss revealed a novel splice site variant (c.1421+2T>C, p.?) that disrupts the splice donor site and a novel frameshift variant (c.1041dup, p.Ser348Glnfs*2) in the gene CDC14A, respectively. To evaluate the pathogenicity of both loss-of-function variants, we analyzed the effects of both variants on the RNA-level. The splice variant was characterized using a minigene assay. Altered expression levels due to the c.1041dup variant were assessed using RT-qPCR. In summary, cDNA analysis confirmed that the c.1421+2T>C variant activates a cryptic splice site, resulting in a truncated transcript (c.1414_1421del, p.Val472Leufs*20) and the c.1041dup variant results in a defective transcript that is likely degraded by nonsense-mediated mRNA decay. The present study functionally characterizes two variants and provides further confirmatory evidence that CDC14A is associated with a rare form of hereditary hearing loss. MDPI 2020-01-02 /pmc/articles/PMC6982189/ /pubmed/31906439 http://dx.doi.org/10.3390/ijms21010311 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Doll, Julia
Kolb, Susanne
Schnapp, Linda
Rad, Aboulfazl
Rüschendorf, Franz
Khan, Imran
Adli, Abolfazl
Hasanzadeh, Atefeh
Liedtke, Daniel
Knaup, Sabine
Hofrichter, Michaela AH
Müller, Tobias
Dittrich, Marcus
Kong, Il-Keun
Kim, Hyung-Goo
Haaf, Thomas
Vona, Barbara
Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients
title Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients
title_full Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients
title_fullStr Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients
title_full_unstemmed Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients
title_short Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients
title_sort novel loss-of-function variants in cdc14a are associated with recessive sensorineural hearing loss in iranian and pakistani patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982189/
https://www.ncbi.nlm.nih.gov/pubmed/31906439
http://dx.doi.org/10.3390/ijms21010311
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