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

被引:11
作者
Doll, Julia [1 ]
Kolb, Susanne [1 ]
Schnapp, Linda [1 ]
Rad, Aboulfazl [2 ]
Ruschendorf, Franz [4 ]
Khan, Imran [5 ]
Adli, Abolfazl [2 ]
Hasanzadeh, Atefeh [2 ]
Liedtke, Daniel [1 ]
Knaup, Sabine [1 ]
Hofrichter, Michaela A. H. [1 ]
Mueller, Tobias [6 ]
Dittrich, Marcus [1 ,6 ]
Kong, Il-Keun [7 ]
Kim, Hyung-Goo [8 ]
Haaf, Thomas [1 ]
Vona, Barbara [1 ,3 ]
机构
[1] Julius Maximilians Univ, Inst Human Genet, D-97074 Wurzburg, Germany
[2] Sabzevar Univ Med Sci, Cellular & Mol Res Ctr, Sabzevar 009851, Iran
[3] Eberhard Karls Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen Hearing Res Ctr, D-72076 Tubingen, Germany
[4] Max Delbruck Ctr Mol Med Helmholtz Assoc, D-13125 Berlin, Germany
[5] Bacha Khan Univ, Dept Chem, Khyber Pakhtunkhawa 24420, Pakistan
[6] Julius Maximilians Univ, Inst Bioinformat, D-97074 Wurzburg, Germany
[7] Gyeongsang Natl Univ, Inst Agr & Life Sci, Div Appl Life Sci BK21plus, Dept Anim Sci, Jinju 52828, South Korea
[8] Hamad Bin Khalifa Univ, Neurol Disorders Res Ctr, Qatar Biomed Res Inst, Doha 34110, Qatar
关键词
CDC14A; DFNB32; autosomal recessive hearing loss; exome sequencing; splicing; frameshift; non-sense mediated mRNA decay; PHOSPHATASE; IDENTIFICATION; MUTATIONS; FRAMEWORK; DISEASE; DECAY;
D O I
10.3390/ijms21010311
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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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页数:14
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