# Role of Kir4.1 Channel in Auditory Function: Impact on Endocochlear Potential and Hearing Loss
## 4 Discussion
### Kir4.1 Channel
#### 4.3.5 Pathophysiology
The striatal expression of KCNJ10 protein, in patients affected by EVA and Pendred syndrome (EVA/PS), is lowered by the combination of SLC26A4 haploinsufficiency and oxidative stress. Due to the decrease in KCNJ10 expression, marginal cells in the stria vascularis receive less K\({}^{+}\). Consequently, these cells decrease the rate of K\({}^{+}\) secretion. This self-limiting mechanism could be the reason for intermittent recovery of hearing thresholds in patients with EVA/PS, which results in fluctuating and progressive hearing loss [50]. New insights into the pathogenesis of EVA/PS can be gained from this paradigm, as this suggests that if the strial expressionof KCNJ10 can be maintained, controlling endolymph pH or limiting oxidative stress through medical therapy may be a way to prevent hearing loss in some individuals with the EVA/PS phenotype. The genetic basis of EVA in patients with hearing loss (HL) was determined by investigating genomic DNA mutations using a custom panel of HL genes that included 237 genes related to hearing loss (HL) or a clinical exome [50]. The study by [PERSON] and colleagues reported that 74% of patients investigated for inner ear malformations and hearing loss had causal genetic variants: two pathogenic variants were found in the SLC26A4 gene in approximately half of the patients, and one of these patients had a Caucasian EVA haplotype (CEVA) well; patients with only one pathogenic variant in the SLC26A4 gene were often diagnosed with CEVA; novel pathogenic variants of the EYA1 gene causing cochlear hypoplasia were identified in two individuals with phenotypes that correspond to branchio-oto-renal spectrum disorder (BOR); and a new variant with unknown significance of CHD7 was discovered in a patient; no pathogenic mutations in the KCNJ10 and FOXI1 genes were identified [58]. [PERSON] et al. reported similar findings ten years ago, concluding that there is no significant link between these two genes and the onset of Pendred syndrome with EVA [59]. In a study with 32 Chinese patients with pathogenic SLC26A4 mutations, no potential pathogenic mutations were identified in the FOXI1 or KCNJ10 genes: amino acid changes were not present in either of the FOXI1 mutations, c.279G.A (p.R93R) or c.1044T.C (p.Y348Y), or the KCNJ10 mutation, c.1053C.T (p.D351D) [60]. [PERSON] et al. found that 25 patients with unilateral hearing impairment and ipsilateral EVA did not have mutations in FOXI1 and KCNJ10 genes [61]. In conclusion, it is uncertain whether digenic inheritance of PS can occur due to single allele mutations in both KCNJ10 and SLC26A4. [PERSON] et al. described four adult patients with EAST/SeSAME syndrome with homozygous missense mutation p.Ala167 Val (identified in two siblings) and homozygous frameshift mutations p.Asn232 GInfs*14 and p.Gly275 Vafs*7 (both born from consanguineous parents, first cousins). These mutation predictions were made using in silico modeling and bioinformatics, which indicated that patients who had truncated mutations had more serious consequences: tubulopathy and neurological symptoms associated with severe epilepsy [62]. In an _in vitro_ study, Kir4.1 has been characterized by new mutations that appear linked to EAST/SeSAME syndrome [25; 63]. Radiotracer efflux and inside-out membrane patch clamping were performed on COSm6 cells expressing homomeric Kir4.1 or heteromeric Kir4.1/Kir5.1 channels, to investigate the functional significance of the reported mutations in the patients. Although all mutations affected channel function, the underlying mechanisms were not the same. R65P, T164I, and R297C played a crucial role in pH sensing and pore gating by causing an alkaline shift in pH sensitivity. A disruption occurred in the intersubunit salt bridge in R297C. G77R may experience changes in channel structure or gating due to the introduction of a positive charge in the bilayer. A167V had no impact on channel properties, but could cause decreased surface expression in A167V/R297C.