title: Cantú syndrome is caused by mutations in ABCC9.
abstract: Cantú syndrome is a rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. Using an exome-sequencing approach applied to one proband-parent trio and three unrelated single cases, we identified heterozygous mutations in ABCC9 in all probands. With the inclusion of the remaining cohort of ten individuals with Cantú syndrome, a total of eleven mutations in ABCC9 were found. The de novo occurrence in all six simplex cases in our cohort substantiates the presence of a dominant disease mechanism. All mutations were missense, and several mutations affect Arg1154. This mutation hot spot lies within the second type 1 transmembrane region of this ATP-binding cassette transporter protein, which may suggest an activating mutation. ABCC9 encodes the sulfonylurea receptor (SUR) that forms ATP-sensitive potassium channels (K(ATP) channels) originally shown in cardiac, skeletal, and smooth muscle. Previously, loss-of-function mutations in this gene have been associated with idiopathic dilated cardiomyopathy type 10 (CMD10). These findings identify the genetic basis of Cantú syndrome and suggest that this is a new member of the potassium channelopathies.
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, The Netherlands.
authors.forename: Bregje W M
authors.initials: BW
authors.lastname: van Bon
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.forename: Heiko
authors.initials: H
authors.lastname: Reutter
authors.forename: John R
authors.initials: JR
authors.lastname: Ostergaard
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tsiakas
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Metin
authors.initials: M
authors.lastname: Eser
authors.forename: Nienke
authors.initials: N
authors.lastname: Wieskamp
authors.forename: Petra
authors.initials: P
authors.lastname: de Vries
authors.forename: Marloes
authors.initials: M
authors.lastname: Steehouwer
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D006332:Cardiomegaly / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D019066:Facies; D005260:Female; D005799:Genes, Dominant; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D006983:Hypertrichosis / Q000235:genetics*; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics*; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D017422:Sequence Analysis, DNA; D064233:Sulfonylurea Receptors
chemical_list: C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors