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Open AccessArticle

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

1
Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany
2
Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar 009851, Iran
3
Tübingen Hearing Research Centre, Department of Otorhinolaryngology, Head and Neck Surgery, Eberhard Karls University, 72076 Tübingen, Germany
4
Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
5
Department of Chemistry, Bacha Khan University, Charsadda, Khyber Pakhtunkhawa 24420, Pakistan
6
Institute of Bioinformatics, Julius Maximilians University, 97074 Würzburg, Germany
7
Department of Animal Science, Division of Applied Life Science (BK21plus), Institute of Agriculture and Life Science, Gyeongsang National University, Jinju 52828, Korea
8
Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha 34110, Qatar
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(1), 311; https://doi.org/10.3390/ijms21010311
Received: 12 December 2019 / Revised: 28 December 2019 / Accepted: 31 December 2019 / Published: 2 January 2020
(This article belongs to the Collection Feature Papers in Molecular Genetics and Genomics)
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. View Full-Text
Keywords: CDC14A; DFNB32; autosomal recessive hearing loss; exome sequencing; splicing; frameshift; non-sense mediated mRNA decay CDC14A; DFNB32; autosomal recessive hearing loss; exome sequencing; splicing; frameshift; non-sense mediated mRNA decay
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MDPI and ACS Style

Doll, J.; Kolb, S.; Schnapp, L.; Rad, A.; Rüschendorf, F.; Khan, I.; Adli, A.; Hasanzadeh, A.; Liedtke, D.; Knaup, S.; Hofrichter, M.A.; Müller, T.; Dittrich, M.; Kong, I.-K.; Kim, H.-G.; Haaf, T.; Vona, B. Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients. Int. J. Mol. Sci. 2020, 21, 311. https://doi.org/10.3390/ijms21010311

AMA Style

Doll J, Kolb S, Schnapp L, Rad A, Rüschendorf F, Khan I, Adli A, Hasanzadeh A, Liedtke D, Knaup S, Hofrichter MA, Müller T, Dittrich M, Kong I-K, Kim H-G, Haaf T, Vona B. Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients. International Journal of Molecular Sciences. 2020; 21(1):311. https://doi.org/10.3390/ijms21010311

Chicago/Turabian Style

Doll, Julia; Kolb, Susanne; Schnapp, Linda; Rad, Aboulfazl; Rüschendorf, Franz; Khan, Imran; Adli, Abolfazl; Hasanzadeh, Atefeh; Liedtke, Daniel; Knaup, Sabine; Hofrichter, Michaela A.; Müller, Tobias; Dittrich, Marcus; Kong, Il-Keun; Kim, Hyung-Goo; Haaf, Thomas; Vona, Barbara. 2020. "Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients" Int. J. Mol. Sci. 21, no. 1: 311. https://doi.org/10.3390/ijms21010311

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