Dominant missense mutations in ABCC9 cause Cantú syndrome

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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 (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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Figure 1: Clinical presentation of subjects with Cantú syndrome and mutations in ABCC9.
Figure 2: Topology and biophysical effect of ABCC9 mutations.

Change history

  • 03 June 2012

    In the version of this article initially published online, author David J. Amor's name was given incorrectly as David J.D. Amor. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

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.

Author information

J.J.T.v.H., P.A.T., D.J.A., L.C.W., E.P.K., C.L.S.T., D.S., S.G.-M., M.M.L., A.R., F.W.A., H.M.B., M.E.S., I.J.S., S.F.S., J.J.v.d.S. and M.M.v.H. characterized individuals with Cantú syndrome and collected clinical data. M.H., K.D., I.R., W.P.K. and G.v.H. performed genetic studies, and M.H., S.v.L. and I.J.N. performed next-generation sequencing data analysis. H.V. and G.V. performed protein modeling studies. H.T., M.B.R. and M.A.G.v.d.H. designed and performed patch clamp experiments. G.v.H., M.H. and J.J.T.v.H. prepared the final manuscript. M.M.v.H., N.V.K., W.P.K., G.v.H. and E.C. supervised the study. All authors critically contributed to the study design and the manuscript.

Correspondence to Gijs van Haaften or Edwin Cuppen.

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The authors declare no competing financial interests.

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Supplementary Tables 1–5, Supplementary Figures 1 and 2 and Supplementary Note (PDF 3209 kb)

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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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