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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number99
JournalExperimental and Molecular Medicine
Volume51
Issue number8
DOIs
Publication statusPublished - 2019 Aug 1

Fingerprint

Audition
Hearing Loss
Databases
Porins
Mutation
Potassium Channels
Genetic Testing
Protein Transport
Gene Frequency
Potassium
Amino Acids
Screening
Proteins
Genes
Population

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Jung, Jinsei ; Lin, Haiyue ; Koh, Young Ik ; Ryu, Kunhi ; Lee, Joon Suk ; Rim, John Hoon ; Choi, Hye Ji ; Lee, Hak Joon ; Kim, Hye Youn ; Yu, Seyoung ; Jin, Hyunsoo ; Lee, Ji Hyun ; Lee, Min Goo ; Namkung, Wan ; Choi, Jae Young ; Gee, Heon Yung. / Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment. In: Experimental and Molecular Medicine. 2019 ; Vol. 51, No. 8.
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title = "Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment",
abstract = "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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Jung, J, Lin, H, Koh, YI, Ryu, K, Lee, JS, Rim, JH, Choi, HJ, Lee, HJ, Kim, HY, Yu, S, Jin, H, Lee, JH, Lee, MG, Namkung, W, Choi, JY & Gee, HY 2019, 'Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment', Experimental and Molecular Medicine, vol. 51, no. 8, 99. https://doi.org/10.1038/s12276-019-0300-9

Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment. / Jung, Jinsei; Lin, Haiyue; Koh, Young Ik; Ryu, Kunhi; Lee, Joon Suk; Rim, John Hoon; Choi, Hye Ji; Lee, Hak Joon; Kim, Hye Youn; Yu, Seyoung; Jin, Hyunsoo; Lee, Ji Hyun; Lee, Min Goo; Namkung, Wan; Choi, Jae Young; Gee, Heon Yung.

In: Experimental and Molecular Medicine, Vol. 51, No. 8, 99, 01.08.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment

AU - Jung, Jinsei

AU - Lin, Haiyue

AU - Koh, Young Ik

AU - Ryu, Kunhi

AU - Lee, Joon Suk

AU - Rim, John Hoon

AU - Choi, Hye Ji

AU - Lee, Hak Joon

AU - Kim, Hye Youn

AU - Yu, Seyoung

AU - Jin, Hyunsoo

AU - Lee, Ji Hyun

AU - Lee, Min Goo

AU - Namkung, Wan

AU - Choi, Jae Young

AU - Gee, Heon Yung

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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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