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

International Journal of Molecular Sciences

Aboulfazl Rad¹  Atefeh Hasanzadeh¹  Abolfazl Adli¹  Il-Keun Kong²  Imran Khan³  Tobias Müller⁴  Daniel Liedtke⁵  Julia Doll⁵  Barbara Vona⁵  Sabine Knaup⁵  Thomas Haaf⁵  Marcus Dittrich⁵  Linda Schnapp⁵  MichaelaAH Hofrichter⁵  Susanne Kolb⁵  Franz Rüschendorf⁶  Hyung-Goo Kim⁷ 

[1] Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar 009851, Iran;Department of Animal Science, Division of Applied Life Science (BK21plus), Institute of Agriculture and Life Science, Gyeongsang National University, Jinju 52828, Korea;Department of Chemistry, Bacha Khan University, Charsadda, Khyber Pakhtunkhawa 24420, Pakistan;Institute of Bioinformatics, Julius Maximilians University, 97074 Würzburg, Germany;Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany;Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany;Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha 34110, Qatar;

关键词: cdc14a;    dfnb32;    autosomal recessive hearing loss;    exome sequencing;    splicing;    frameshift;    non-sense mediated mrna decay;   

DOI  :  10.3390/ijms21010311

来源: DOAJ

【 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.

【 授权许可】

Unknown