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Pendred Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
There is tangible evidence that mutations in the FOXI1 gene on chromosome 5q35.1 encoding forkhead box protein I1 and the KCNJ10 gene on chromosome 1q23.2 encoding the ATP-sensitive inward rectifier potassium channel 10 may be implicated in about 2% of non-classic Pendred syndrome (also known as nonsyndromic enlarged vestibular aqueduct [NSEVA]), but not classic Pendred syndrome. Further, biallelic KCNJ10 pathogenic variants are involved in SeSAME syndrome (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance) and EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) [17,18].
Anatomy of the Cochlea and Vestibular System: Relating Ultrastructure to Function
Published in John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed, Paediatrics, The Ear, Skull Base, 2018
In addition, these cells are thought to play a crucial role in cochlear homeostasis. They take up K+ from the extracellular spaces around the hair cells127–129 and ferry it out of the sensory epithelium by an intracellular route through the intercellular coupling provided by the large gap junctions (Figure 47.7q).48 Removal of K+ from the spaces around the hair cell bodies is crucial, not only to prevent accumulation of K+ that would disrupt ionic gradients and thus normal transduction, but also because high extracellular K+ is toxic to the cells and OHCs are especially sensitive. Consistent with this model, mutations in the genes that encode the K+-transporting proteins present in the membranes of the Deiters’ cells, KCC4 and Kir4.1 (KCNJ10), cause hearing impairment and death of hair cells.127,130
Potassium channels as prominent targets and tools for the treatment of epilepsy
Published in Expert Opinion on Therapeutic Targets, 2021
Mutations of inward rectifying channels are relatively rare in epileptic patients and mostly involve astrocytic Kir4.1. Kir4.1 channels are expressed primarily in astrocytes and support the spatial buffering of potassium. The missense variations in Kir4.1 lead to disruption of astrocyte-dependent spatial buffering of potassium and its pathological accumulation, suggesting a potential mechanism of seizure susceptibility [104]. Loss-of-function mutations in KCNJ10 gene encoding Kir4.1 channel was linked to EAST (epilepsy, ataxia, sensorineural deafness, and tubulopathy) syndrome [105]. Brain abnormalities in EAST syndrome include mild cerebellar atrophy and intramyelinic edema, which may be important diagnostic clues for suspecting this condition in MRI [106]. Single nucleotide polymorphisms of genes encoding Kir4.1 subunits were found in patients with focal and generalized epilepsies including TLE [104,107]. Reduction in glial Kir4.1 function without alterations in activity of Kv channels was found in the tissue of patients with intractable epilepsy and hippocampal sclerosis [108,109]. Mutations of Kir4.1 channels have been detected in patients with the autism-epilepsy phenotype [110], suggesting that dysfunction of the channels may be a common mechanism contributing to seizures and behavioral features of Autism Spectrum Disorders. Mutations in Kir6.2 (KATP) channels are associated with DEND syndrome (infantile diabetes, developmental delay and epilepsy) [111–113].
Cortical projection neurons as a therapeutic target in multiple sclerosis
Published in Expert Opinion on Therapeutic Targets, 2020
Tatjana Beutel, Julia Dzimiera, Hannah Kapell, Maren Engelhardt, Achim Gass, Lucas Schirmer
Moreover, cortical neuron dysfunction and damage can be the consequence of sustained oxidative injury as well as retrograde neurodegeneration through accumulating WM pathology as pointed out above [3,115]. Focusing on ionic imbalance, potassium channels such as glial Kir4.1 encoded by KCNJ10 have been reported to show substantial dysregulation at both protein and transcript levels [12,116]. Kir4.1, exclusively expressed by oligodendrocytes and astrocytes, is key for the extracellular potassium homeostasis in the CNS by providing an influx of potassium into myelinating oligodendrocytes and astrocytes [117]. Interestingly, an ablation of astrocyte and oligodendrocyte-encoded KCNJ10 leads to an increase of extracellular potassium, which raises the neuronal RMP and excitability and results in neurological symptoms such as epileptic seizures and axonal degeneration [118–120]. In addition, a loss of glial Kir4.1 channels has been reported in MS lesions [121] and a subset of MS patients might have serum antibodies against Kir4.1 channels [122].
Novel mutation in the KCNJ10 gene in three siblings with seizures, ataxia and no electrolyte abnormalities
Published in Journal of Neurogenetics, 2018
Muna A. Al Dhaibani, Ayman W. El-Hattab, Kathryn B. Holroyd, Jennifer Orthmann-Murphy, Valerie A. Larson, Khurram A. Siddiqui, Miklos Szolics, Nicoline Schiess
Whole exome sequencing of the proband was performed at Baylor Miraca Genetics laboratories and showed a novel homozygous missense mutation c.179T > C (p.I60T) in the KCNJ10 gene. In silico, this mutation was predicted to be deleterious by both SIFT and Polyphen-2. Both parents were found to be carriers (heterozygous). Testing of all siblings revealed two other affected homozygous siblings, two unaffected siblings who were heterozygous and two unaffected siblings who were negative. The segregation of the phenotype with the homozygous mutations further supported the pathogenicity of the c.179T > C (p.I60T) mutation. The c.179T > C (p.I60T) variant in KCNJ10 has not been reported in general population. Besides this homozygous mutation in the KCNJ10 gene, no other variants explaining the phenotype were detected.