Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783491258222641152 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6982189 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT dolljulia novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT kolbsusanne novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT schnapplinda novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT radaboulfazl novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT ruschendorffranz novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT khanimran novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT adliabolfazl novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT hasanzadehatefeh novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT liedtkedaniel novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT knaupsabine novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT hofrichtermichaelaah novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT mullertobias novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT dittrichmarcus novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT kongilkeun novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT kimhyunggoo novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT haafthomas novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients AT vonabarbara novellossoffunctionvariantsincdc14aareassociatedwithrecessivesensorineuralhearinglossiniranianandpakistanipatients |