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 language | English |
|---|---|
| Article number | 99 |
| Journal | Experimental and Molecular Medicine |
| Volume | 51 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2019 Aug 1 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry
Cite this
}
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 journal › Article
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.
UR - http://www.scopus.com/inward/record.url?scp=85070987834&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070987834&partnerID=8YFLogxK
U2 - 10.1038/s12276-019-0300-9
DO - 10.1038/s12276-019-0300-9
M3 - Article
C2 - 31434872
AN - SCOPUS:85070987834
VL - 51
JO - Experimental and Molecular Medicine
JF - Experimental and Molecular Medicine
SN - 1226-3613
IS - 8
M1 - 99
ER -