Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Jung, Jinsei; Choi, Hyun; Koh, Young; Rim, John; Choi, Hye; Kim, Sung; Lee, Jae; An, Jieun; Kim, Ami; Lee, Joon; Joo, Sun; Yu, Seyoung; Choi, Jae; Kang, Tong; Gee, Heon
• Is Part Of: Scientific reports. Volume 8:Issue 1(2018)
• Page Start: 1
• Page End: 11
• Publication Date: 2018-12
• Subjects: Natural history -- Research -- Periodicals; Biology -- Research -- Periodicals; Physical sciences -- Research -- Periodicals; Earth sciences -- Research -- Periodicals; Environmental sciences -- Research -- Periodicals; 502.85
• DOI: 10.1038/s41598-018-34876-9
• Languages: English
• ISSNs: 2045-2322

Abstract

Abstract Mutations in potassium voltage-gated channel subfamily Q member 4 (KCNQ4 ) are etiologically linked to a type of nonsyndromic hearing loss, deafness nonsyndromic autosomal dominant 2 (DFNA2). We performed whole-exome sequencing for 98 families with hearing loss and found mutations inKCNQ4 in five families. In this study, we characterized two novel mutations inKCNQ4 : a missense mutation (c.796G>T; p.Asp266Tyr) and an in-frame deletion mutation (c.259_267del; p.Val87_Asn89del). p.Asp266Tyr located in the channel pore region resulted in early onset and moderate hearing loss, whereas p.Val87_Asn89del located in the N-terminal cytoplasmic region resulted in late onset and high frequency-specific hearing loss. When heterologously expressed in HEK 293 T cells, both mutant proteins did not show defects in protein trafficking to the plasma membrane or in interactions with wild-type (WT) KCNQ4 channels. Patch-clamp analysis demonstrated that both p.Asp266Tyr and p.Val87_Asn89del mutant channels lost conductance and were completely unresponsive to KCNQ activators, such as retigabine, zinc pyrithione, and ML213. Channels assembled from WT-p.Asp266Tyr concatemers, like those from WT-WT concatemers, exhibited conductance and responsiveness to KCNQ activators. However, channels assembled from WT-p.Val87_Asn89del concatemers showed impaired conductance, suggesting that p.Val87_Asn89del caused complete loss-of-function with a strong dominant-negative effect on functional WT channels. Therefore, the main pathological mechanism may be related to loss of K+ channel activity, not defects in trafficking.