title: A de novo mutation in KCNN3 associated with autosomal dominant idiopathic non-cirrhotic portal hypertension.
abstract: Non-cirrhotic portal hypertension is characterized by histopathological abnormalities in the liver, mostly affecting small intrahepatic portal veins that cause portal hypertension in the absence of cirrhosis. It can be secondary to coagulation disorders or toxic agents. However, most cases are idiopathic non-cirrhotic portal hypertension (INCPH) and familial cases are rare. We report a family in which a father and three of his four children conceived with three different mothers are affected by INCPH. Whole exome and Sanger sequencing showed the father to have a de novo single nucleotide substitution c.1348G>C in the KCNN3 gene that was transmitted to all three of his affected offspring. The KCNN3 gene encodes small conductance calcium-activated potassium (SK) channel 3. SK channels are involved in the regulation of arterial and venous vascular tone by causing smooth muscle relaxation on activation. No data exist on the expression and function of SK channels in portal veins. The autosomal dominant inheritance in this unique pedigree and the single de novo mutation identified, strongly suggests that KCNN3 mutations have a pathogenetic role in INCPH.
authors.affiliation: Department of Pediatric Gastroenterology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Bart G P
authors.initials: BG
authors.lastname: Koot
authors.affiliation: Department of Medical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marielle
authors.initials: M
authors.lastname: Alders
authors.affiliation: Department of Pathology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joanne
authors.initials: J
authors.lastname: Verheij
authors.affiliation: Department of Hepatology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.affiliation: Department of Pediatric Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: j.m.cobben@amc.uva.nl.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Cobben
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D006801:Humans; D006975:Hypertension, Portal / Q000235:genetics*; D007223:Infant; D008099:Liver / Q000473:pathology; D008297:Male; D009154:Mutation; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics*
chemical_list: C406328:KCNN3 protein, human; D051640:Small-Conductance Calcium-Activated Potassium Channels
keywords: Dominant inheritance; Idiopathic non-cirrhotic portal hypertension; KCNN3; Single nucleotide substitution; Small conductance calcium-activated potassium channel; Whole exome sequencing