title: Dominant missense mutations in ABCC9 cause Cantú syndrome.
abstract: 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.
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Harakalova
authors.forename: Jeske J T
authors.initials: JJ
authors.lastname: van Harssel
authors.forename: Paulien A
authors.initials: PA
authors.lastname: Terhal
authors.forename: Stef
authors.initials: S
authors.lastname: van Lieshout
authors.forename: Karen
authors.initials: K
authors.lastname: Duran
authors.forename: Ivo
authors.initials: I
authors.lastname: Renkens
authors.forename: David J
authors.initials: DJ
authors.lastname: Amor
authors.forename: Louise C
authors.initials: LC
authors.lastname: Wilson
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Kirk
authors.forename: Claire L S
authors.initials: CL
authors.lastname: Turner
authors.forename: Debbie
authors.initials: D
authors.lastname: Shears
authors.forename: Sixto
authors.initials: S
authors.lastname: Garcia-Minaur
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Lees
authors.forename: Alison
authors.initials: A
authors.lastname: Ross
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.forename: Gert
authors.initials: G
authors.lastname: Vriend
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takanari
authors.forename: Martin B
authors.initials: MB
authors.lastname: Rook
authors.forename: Marcel A G
authors.initials: MA
authors.lastname: van der Heyden
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.forename: Hans M
authors.initials: HM
authors.lastname: Breur
authors.forename: Marielle E
authors.initials: ME
authors.lastname: Swinkels
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Scurr
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Smithson
authors.forename: Nine V
authors.initials: NV
authors.lastname: Knoers
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: van der Smagt
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Nijman
authors.forename: Wigard P
authors.initials: WP
authors.lastname: Kloosterman
authors.forename: Mieke M
authors.initials: MM
authors.lastname: van Haelst
authors.forename: Gijs
authors.initials: G
authors.lastname: van Haaften
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D006332:Cardiomegaly / Q000235:genetics*; D002461:Cell Line, Transformed; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D006983:Hypertrichosis / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D054086:KATP Channels / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors; D055815:Young Adult
chemical_list: C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors