Dominant missense mutations in ABCC9 cause Cantú syndrome

Magdalena Harakalova, Jeske J T van Harssel, Paulien A Terhal, Stef van Lieshout, Karen Duran, Ivo Renkens, David J Amor, Louise C Wilson, Edwin P Kirk, Claire L S Turner, Debbie Shears, Sixto Garcia-Minaur, Melissa M Lees, Alison Ross, Hanka Venselaar, Gert Vriend, Hiroki Takanari, Martin B Rook, Marcel A G van der Heyden, Folkert W AsselbergsHans M Breur, Marielle E Swinkels, Ingrid J Scurr, Sarah F Smithson, Nine V Knoers, Jasper J van der Smagt, Isaac J Nijman, Wigard P Kloosterman, Mieke M van Haelst, Gijs van Haaften, Edwin Cuppen

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)793-6
Number of pages4
JournalNature Genetics
Volume44
Issue number7
DOIs
Publication statusPublished - 18 May 2012

Cite this

Harakalova, M., van Harssel, J. J. T., Terhal, P. A., van Lieshout, S., Duran, K., Renkens, I., ... Cuppen, E. (2012). Dominant missense mutations in ABCC9 cause Cantú syndrome. Nature Genetics, 44(7), 793-6. https://doi.org/10.1038/ng.2324