Association between the serum concentrations and mutational status of IL‑8, IL‑27 and VEGF and the expression levels of the hERG potassium channel gene in patients with colorectal cancer

Abstract Background Epilepsy is one of the most common and heterogeneous neurological diseases. The main clinical signs of the disease are repeated symptomatic or idiopathic epileptic seizures of both convulsive and non-convulsive nature that develop against a background of lost or preserved consciousness. The genetic component plays a large role in the etiology of idiopathic forms of epilepsy. The study of the molecular genetic basis of neurological disorders has led to a rapidly growing number of gene mutations known to be involved in hereditary ion channel dysfunction. The aim of this research was to evaluate the involvement of single-nucleotide variants that modify the function of genes (SCN1A, KCNT1, KCNTС1, and KCNQ2) encoding sodium and potassium ion channel polypeptides in the development of epilepsy. Results De novo mutations in the sodium channel gene SCN1A c.5347G>A (p. Ala1783Thr) were detected in two patients with Dravet syndrome, with a deletion in exon 26 found in one. Three de novo mutations in the potassium channel gene KCNT1 c.2800G>A (p. Ala934Thr), were observed in two patients with temporal lobe epilepsy (TLE) and one patient with residual encephalopathy. Moreover, a control cohort matched to the case cohort did not reveal any SNVs among conditionally healthy individuals, supporting the pathogenic significance of the studied SNVs. Conclusion Our results are supported by literature data showing that the sodium ion channel gene SCN1A c.5347G>A mutation may be involved in the pathogenesis of Dravet syndrome. We also note that the c.2800G>A mutation in the potassium channel gene KCNT1 can cause not only autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) but also other forms of epilepsy. To treat pathogenetic mutations that accelerate the function of sodium and potassium ion channels, we recommend ion channel blockade drug therapy.

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Association analysis of a highly polymorphic CAG Repeat in the human potassium channel gene KCNN3 and migraine susceptibility

BMC Medical Genetics ◽

10.1186/1471-2350-6-32 ◽

2005 ◽

Vol 6 (1) ◽

Cited By ~ 10

Author(s):

Robert Curtain ◽

James Sundholm ◽

Rod Lea ◽

Mick Ovcaric ◽

John MacMillan ◽

...

Keyword(s):

Potassium Channel ◽

Association Analysis ◽

Cag Repeat ◽

Channel Gene ◽

Potassium Channel Gene

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Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes

Cancers ◽

10.3390/cancers11070983 ◽

2019 ◽

Vol 11 (7) ◽

pp. 983 ◽

Cited By ~ 3

Author(s):

Otília Menyhart ◽

Tatsuhiko Kakisaka ◽

Lőrinc Sándor Pongor ◽

Hiroyuki Uetake ◽

Ajay Goel ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Gene Expression Data ◽

Drug Targets ◽

Therapeutic Targets ◽

Independent Set ◽

Driver Mutations ◽

Expression Data ◽

Expression Levels ◽

Mutational Status

Background: Numerous driver mutations have been identified in colorectal cancer (CRC), but their relevance to the development of targeted therapies remains elusive. The secondary effects of pathogenic driver mutations on downstream signaling pathways offer a potential approach for the identification of therapeutic targets. We aimed to identify differentially expressed genes as potential drug targets linked to driver mutations. Methods: Somatic mutations and the gene expression data of 582 CRC patients were utilized, incorporating the mutational status of 39,916 and the expression levels of 20,500 genes. To uncover candidate targets, the expression levels of various genes in wild-type and mutant cases for the most frequent disruptive mutations were compared with a Mann–Whitney test. A survival analysis was performed in 2100 patients with transcriptomic gene expression data. Up-regulated genes associated with worse survival were filtered for potentially actionable targets. The most significant hits were validated in an independent set of 171 CRC patients. Results: Altogether, 426 disruptive mutation-associated upregulated genes were identified. Among these, 95 were linked to worse recurrence-free survival (RFS). Based on the druggability filter, 37 potentially actionable targets were revealed. We selected seven genes and validated their expression in 171 patient specimens. The best independently validated combinations were DUSP4 (p = 2.6 × 10−12) in ACVR2A mutated (7.7%) patients; BMP4 (p = 1.6 × 10−04) in SOX9 mutated (8.1%) patients; TRIB2 (p = 1.35 × 10−14) in ACVR2A mutated patients; VSIG4 (p = 2.6 × 10−05) in ANK3 mutated (7.6%) patients, and DUSP4 (p = 7.1 × 10−04) in AMER1 mutated (8.2%) patients. Conclusions: The results uncovered potentially druggable genes in colorectal cancer. The identified mutations could enable future patient stratification for targeted therapy.

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