A single nucleotide substitution (SNP) c.1348G>C in the KCNN3 gene was found in a father with INCPH and three of his children that were tested with Sanger- and whole-exome sequencing. These three children had developed signs of INCPH in the first ten years of their lives. A full sister of one of the girls had no complaints and did not participate in the examinations. Ultrasound and liver tests of the paternal grandparents showed no abnormalities of the liver. (Koot et al. 2015)
KCNN genes are expressed in neurons, epithelium, endothelium of the vasculature, and several types of smooth muscle. The SK3 channel, which is a gene product of the KCNN3 gene, is involved in vascular tone- and blood pressure regulation.
Calcium-induced activation of the SK3 channel will cause hyperpolarization of endothelial cells, resulting in hyperpolarization of the adjacent muscle cell, which is also known as an endothelium-derived hyperpolarizing factor (EDHF). This hyperpolarization of the muscle cells will then result in dilation in resistance arteries (Ledoux et al. 2006; Kohler et al. 2010).
The level of SK3 channel expression in endothelial cells was found to be important for vascular tone and blood pressure in mice. (Taylor et al. 2003)
Gene transcription:
Two binding sites for the SP1 and SP3 transcription factors are present in the promotor region of the KCNN3 gene in mice. SP1 and SP3 compete to regulate the expression of the KCNN3 gene, influenced by the environment of the promotors. SP1 activates the expression of the gene, and SP3 inhibits the expression of the gene (Pierce et al., 2010; Xiong et al., 2020) . It was found that ERĪ± stimulates the transcription KCNN3 through these transcription factors (Jacobson et al., 2003).