1. Dominant missense mutations in ABCC9 cause Cantu syndrome
- Author
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Wigard P. Kloosterman, Nine V A M Knoers, Edwin P. Kirk, Sarah F. Smithson, Alison Ross, Karen Duran, Ivo Renkens, Ingrid Scurr, Gert Vriend, Claire L. S. Turner, Marielle E M Swinkels, Edwin Cuppen, Isaac J. Nijman, Melissa Lees, Paulien A Terhal, Stef van Lieshout, Louise C. Wilson, Magdalena Harakalova, Marcel A.G. van der Heyden, Folkert W. Asselbergs, Hans M P J Breur, Sixto García-Miñaur, Jasper J. van der Smagt, Jeske J.T. van Harssel, Martin B. Rook, Debbie Shears, Mieke M. van Haelst, Hanka Venselaar, Hiroki Takanari, David J. Amor, Gijs van Haaften, Hubrecht Institute for Developmental Biology and Stem Cell Research, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), and Other departments
- Subjects
Male ,Cantú syndrome ,Potassium Channels ,Genetics and epigenetic pathways of disease [NCMLS 6] ,ATP-Binding Cassette Transporters/genetics ,Receptors, Drug ,Genetic Diseases, X-Linked/genetics ,Sulfonylurea Receptors ,KATP Channels ,Receptors ,Missense mutation ,Exome ,Child ,Exome sequencing ,Cell Line, Transformed ,KATP Channels/genetics ,Genetics ,Inwardly Rectifying/genetics ,Genetic Diseases, X-Linked ,Cardiomegaly/genetics ,Potassium channel ,X-Linked/genetics ,Drug/genetics ,Genetic Diseases ,Child, Preschool ,Hypertrichosis/genetics ,Female ,Receptors, Drug/genetics ,Adult ,Chemical and physical biology [NCMLS 7] ,Protein Structure ,Bioinformatics ,Hypertrichosis ,Mutation, Missense ,Cardiomegaly ,Biology ,Osteochondrodysplasias ,Tertiary/genetics ,Cell Line ,ABCC9 ,Protein Structure, Tertiary/genetics ,Young Adult ,medicine ,Humans ,Genetic Predisposition to Disease ,Potassium Channels, Inwardly Rectifying ,Preschool ,Osteochondrodysplasias/genetics ,Infant, Newborn ,Infant ,Newborn ,medicine.disease ,Osteochondrodysplasia ,Protein Structure, Tertiary ,HEK293 Cells ,Transformed ,Mutation ,Potassium Channels, Inwardly Rectifying/genetics ,Sulfonylurea receptor ,ATP-Binding Cassette Transporters ,Missense - Abstract
Item does not contain fulltext Cantu 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 Cantu 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 Cantu 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 Cantu syndrome.
- Published
- 2012