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.

Mutations in the novel gene FOPV are associated with familial autosomal dominant and non‐familial obliterative portal venopathy

“…The pedigrees of the families reported here are suggestive of autosomal dominant inherited OPV, with incomplete penetrance and variable expressivity. This pattern of inheritance is in accordance with cases of familial autosomal dominant OPV reported recently . Incomplete penetrance and variable expressivity of the disorder is suggested by the variable phenotypic expression of the disease in genetically affected patients, ranging from clinically undetectable disease (Father B. I‐2) to mild and severe diseases in other affected patients.…”

“…Whole exome sequencing identified in both families heterozygous missense variants in a novel gene that we named FOPV but did not identify mutations in other genes previously reported to be associated with OPV . Sanger sequencing confirmed the FOPV mutations.…”

“…A schematic representation of FOPV gene structure is shown in the supporting information section (Figure ). In both families, no mutations were identified in other genes previously reported to be associated with OPV …”

“…Recently, mutations in several genes have been described in familial cases ( KCNN3 , DGUOK ), or in patients with other inherited ( TERT , TERC and other genes of telomere disorders) or developmental ( NOTCH1 and CTC1 related “syndromic cases”) disorders, and Turner syndrome . In reported cases of familial OPV, associated or not with a gene defect, the pattern of inheritance was consistent with, or established as autosomal recessive or dominant . We report on two families in which heterozygous mutations in a novel gene called FOPV (Familial Obliterative Portal Venopathy) are associated with OPV, likely inherited in an autosomal dominant fashion with incomplete penetrance.…”

“…Observations of familial cases of OPV and of association of OPV with genetic disorders suggest a potential role for genetics in, at least, a subgroup of patients with OPV . Recently, mutations in several genes have been described in familial cases ( KCNN3 , DGUOK ), or in patients with other inherited ( TERT , TERC and other genes of telomere disorders) or developmental ( NOTCH1 and CTC1 related “syndromic cases”) disorders, and Turner syndrome . In reported cases of familial OPV, associated or not with a gene defect, the pattern of inheritance was consistent with, or established as autosomal recessive or dominant .…”