ABSTRACT
Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.
Subject(s)
Abnormalities, Multiple/genetics , Channelopathies/genetics , Craniofacial Abnormalities/genetics , Ether-A-Go-Go Potassium Channels/genetics , Fibromatosis, Gingival/genetics , Gain of Function Mutation , Hallux/abnormalities , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Nails, Malformed/genetics , Potassium Channels/genetics , Small-Conductance Calcium-Activated Potassium Channels/genetics , Thumb/abnormalities , Abnormalities, Multiple/pathology , Adolescent , Adult , Channelopathies/pathology , Child , Craniofacial Abnormalities/pathology , Female , Fibromatosis, Gingival/pathology , Hallux/pathology , Hand Deformities, Congenital/pathology , Humans , Intellectual Disability/pathology , Male , Nails, Malformed/pathology , Phenotype , Thumb/pathologySubject(s)
Loeys-Dietz Syndrome/diagnosis , Phenotype , Aged , Female , Humans , Loeys-Dietz Syndrome/genetics , Male , Middle Aged , Mutation , Pedigree , Protein Serine-Threonine Kinases/genetics , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/geneticsABSTRACT
Cantú syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantú syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantú syndrome.
