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 (KATP) 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 KATP 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.
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We thank the families of our subjects for participating in this study. We thank J.A. Sánchez-Chapula (Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima) for providing wild-type KCNJ11 and ABCC9 expression constructs and N. Lansu and E. de Bruijn for technical support. F.W.A. is supported by a clinical fellowship from the Netherlands Organisation for Health Research and Development (ZonMw; 90700342). G.v.H. is supported by a Veni Grant from the Netherlands Organisation for Health Research and Development. This study was financially supported by the Child Health Priority Program of the University Medical Center Utrecht.
The authors declare no competing financial interests.
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Harakalova, M., van Harssel, J., Terhal, P. et al. Dominant missense mutations in ABCC9 cause Cantú syndrome. Nat Genet 44, 793–796 (2012) doi:10.1038/ng.2324
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