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Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment

 Jinsei Jung  ;  Haiyue Lin  ;  Young Ik Koh  ;  Kunhi Ryu  ;  Joon Suk Lee  ;  John Hoon Rim  ;  Hye Ji Choi  ;  Hak Joon Lee  ;  Hye-Youn Kim  ;  Seyoung Yu  ;  Hyunsoo Jin  ;  Ji Hyun Lee  ;  Min Goo Lee  ;  Wan Namkung  ;  Jae Young Choi  ;  Heon Yung Gee 
 Experimental and Molecular Medicine, Vol.51(8) : 99, 2019 
Journal Title
 Experimental and Molecular Medicine 
Issue Date
KCNQ4 is frequently mutated in autosomal dominant non-syndromic hearing loss (NSHL), a typically late-onset, initially high-frequency loss that progresses over time (DFNA2). Most KCNQ4 mutations linked to hearing loss are clustered around the pore region of the protein and lead to loss of KCNQ4-mediated potassium currents. To understand the contribution of KCNQ4 variants to NSHL, we surveyed public databases and found 17 loss-of-function and six missense KCNQ4 variants affecting amino acids around the pore region. The missense variants have not been reported as pathogenic and are present at a low frequency (minor allele frequency < 0.0005) in the population. We examined the functional impact of these variants, which, interestingly, induced a reduction in potassium channel activity without altering expression or trafficking of the channel protein, being functionally similar to DFNA2-associated KCNQ4 mutations. Therefore, these variants may be risk factors for late-onset hearing loss, and individuals harboring any one of these variants may develop hearing loss during adulthood. Reduced channel activity could be rescued by KCNQ activators, suggesting the possibility of medical intervention. These findings indicate that KCNQ4 variants may contribute more to late-onset NSHL than expected, and therefore, genetic screening for this gene is important for the prevention and treatment of NSHL.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hye-Youn(김혜연) ORCID logo https://orcid.org/0000-0003-2090-6427
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Jung, Jinsei(정진세) ORCID logo https://orcid.org/0000-0003-1906-6969
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
Choi, Jae Young(최재영) ORCID logo https://orcid.org/0000-0001-9493-3458
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