# 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 KCNJ10 gene is located on chromosome 1q22-23. Mutations can lead to the synthesis of altered Kir4.1, which can result in hearing loss. To date, it is well documented that it is associated with the development of two syndromes: EAST/SeSAME syndrome and Pendred syndrome [14]. In 2009, [PERSON] and [PERSON] independently identified a rare autosomal recessive syndrome named \"EAST/SeSAME syndrome\", derived from EAST (epilepsy, ataxia, sensorineural deafness, tubulopathy) and SeSAME (seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance) diseases [48; 49]. As defined by the acronym, it is characterized by seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance. It can be identified by sequencing the KCNJ10 gene: it has been documented in all patients with SeSAME coming from four different families, missense or nonsense mutations that affected both alleles. According to evidence, these mutations result in a loss of function in K\({}^{+}\) channels that are related to glia in the brain, in the spinal cord, on the basolateral membrane of the distal nephron, and in the cochlea, where, at this specific site, it is involved in the endolymph homeostasis [49; 50]. The medical literature has reported 16 mutations associated with different clinical characteristics observed even within family members: the most debilitating features are epilepsy and ataxia; seizures generally occur at the beginning of childhood; muscle tone increases with age; and the degree of hearing impairment ranges from mild to severe [48; 51; 52]. Autosomal recessive syndromic deafness caused primarily by SLC26A4 mutations was described in KCNJ10 mutations or deficiencies that could also be associated with an enlarged vestibular aqueduct (EVA) and Pendred syndrome (PDS)/DNFB4 [29; 53]. Hearing loss and a goiter are common symptoms of Pendred syndrome, which is caused by mutations in genes that encode ion transporters and pumps that regulate the pH and ionic composition of the endolymph. These alterations can cause distal renal tubular acidosis, deafness, or non-syndromic early-onset severe-to-profound hearing loss, which is often associated with EVA. About one third of patients experience a fluctuating hearing loss due to enlarged vestibular aqueducts, whether they are syndromic or non-syndromic. The fluctuations may be linked to endolymphic hydrops (an excessive accumulation of endolymph in the cochlea and the vestibular system), but it is still unclear what exactly leads to hearing impairment and the generation of sudden drops [5]. In 2009, 89 patients were screened for a clinical diagnosis of EVA/PS and were known carriers of a single mutation of the SLC26A4 coding sequence [54]. In SLC26A4\(-/-\) mice, the KCNJ10 protein was not expressed, resulting in their lack of endocochlear potential. Intermediate cells protect the stria vascularis themselves from free radical damage by converting CO\({}_{2}\) to HCO\({}_{3}\) and generating glutathione and melanin pigment [55; 56]. The loss of pendrin, which allows the transport of HCO\({}_{3}\) into the endolymph, may result in the alkalinization of intragriatal spaces. Thus, the loss of the KCNJ10 protein in strial intermediate cells can be caused by changes in cytosolic pH and free radical stress. Cytosolic pH and free radicals control the function and expression of other K\({}^{+}\) channels, indicating the metabolic status of the cell [28; 49; 51]. Dearfness may be directly caused by the suppression of the KCNJ10 channel in intermediate strial cells, which is crucial for generating EP, in SLC26A4\(-/-\) mice and patients with Pendred syndrome [29; 53; 55; 57]. [PERSON] et al. [48] have shown that the combination of two mutations, SLC26A4 and KCNJ10, was specifically associated with inner ear dysfunction [54]. The mutations in SLC26A4 lead to hypofunction or haploinsufficiency.