Dominant missense mutations in ABCC9 cause Cantu syndrome

M. Harakalova; J.J. van Harssel; P.A. Terhal; S. van Lieshout; K. Duran; I. Renkens; D.J. Amor; L.C. Wilson; E.P. Kirk; C.L. Turner; D. Shears; S. Garcia-Minaur; M.M. Lees; A. Ross; H. Venselaar; G. Vriend; H. Takanari; M.B. Rook; M.A. van der Heyden; F.W. Asselbergs; H.M. Breur; M.E. Swinkels; I.J. Scurr; S.F. Smithson; N.V. Knoers; J.J. van der Smagt; I.J. Nijman; W.P. Kloosterman; M.M. van Haelst; G. van Haaften; E. Cuppen

doi:10.1038/ng.2324

Dominant missense mutations in ABCC9 cause Cantu syndrome

M. Harakalova, J.J. van Harssel, P.A. Terhal, S. van Lieshout, K. Duran, I. Renkens, D.J. Amor, L.C. Wilson, E.P. Kirk, C.L. Turner, D. Shears, S. Garcia-Minaur, M.M. Lees, A. Ross, H. Venselaar, G. Vriend, H. Takanari, M.B. Rook, M.A. van der Heyden, F.W. AsselbergsH.M. Breur, M.E. Swinkels, I.J. Scurr, S.F. Smithson, N.V. Knoers, J.J. van der Smagt, I.J. Nijman, W.P. Kloosterman, M.M. van Haelst, G. van Haaften, E. Cuppen

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

Abstract

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.

Original language	English
Pages (from-to)	793-796
Journal	Nature Genetics
Volume	44
Issue number	7
DOIs	https://doi.org/10.1038/ng.2324
Publication status	Published - 2012

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Harakalova, M., van Harssel, J. J., Terhal, P. A., van Lieshout, S., Duran, K., Renkens, I., Amor, D. J., Wilson, L. C., Kirk, E. P., Turner, C. L., Shears, D., Garcia-Minaur, S., Lees, M. M., Ross, A., Venselaar, H., Vriend, G., Takanari, H., Rook, M. B., van der Heyden, M. A., ... Cuppen, E. (2012). Dominant missense mutations in ABCC9 cause Cantu syndrome. Nature Genetics, 44(7), 793-796. https://doi.org/10.1038/ng.2324

@article{e7e46b2e76534906b9db30109b368e10,

title = "Dominant missense mutations in ABCC9 cause Cantu syndrome",

abstract = "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.",

author = "M. Harakalova and {van Harssel}, J.J. and P.A. Terhal and {van Lieshout}, S. and K. Duran and I. Renkens and D.J. Amor and L.C. Wilson and E.P. Kirk and C.L. Turner and D. Shears and S. Garcia-Minaur and M.M. Lees and A. Ross and H. Venselaar and G. Vriend and H. Takanari and M.B. Rook and {van der Heyden}, M.A. and F.W. Asselbergs and H.M. Breur and M.E. Swinkels and I.J. Scurr and S.F. Smithson and N.V. Knoers and {van der Smagt}, J.J. and I.J. Nijman and W.P. Kloosterman and {van Haelst}, M.M. and {van Haaften}, G. and E. Cuppen",

note = "Reporting year: 2012",

year = "2012",

doi = "10.1038/ng.2324",

language = "English",

volume = "44",

pages = "793--796",

journal = "Nature Genetics",

issn = "1061-4036",

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Harakalova, M, van Harssel, JJ, Terhal, PA, van Lieshout, S, Duran, K, Renkens, I, Amor, DJ, Wilson, LC, Kirk, EP, Turner, CL, Shears, D, Garcia-Minaur, S, Lees, MM, Ross, A, Venselaar, H, Vriend, G, Takanari, H, Rook, MB, van der Heyden, MA, Asselbergs, FW, Breur, HM, Swinkels, ME, Scurr, IJ, Smithson, SF, Knoers, NV, van der Smagt, JJ, Nijman, IJ, Kloosterman, WP, van Haelst, MM, van Haaften, G & Cuppen, E 2012, 'Dominant missense mutations in ABCC9 cause Cantu syndrome', Nature Genetics, vol. 44, no. 7, pp. 793-796. https://doi.org/10.1038/ng.2324

TY - JOUR

T1 - Dominant missense mutations in ABCC9 cause Cantu syndrome

AU - Harakalova, M.

AU - van Harssel, J.J.

AU - Terhal, P.A.

AU - van Lieshout, S.

AU - Duran, K.

AU - Renkens, I.

AU - Amor, D.J.

AU - Wilson, L.C.

AU - Kirk, E.P.

AU - Turner, C.L.

AU - Shears, D.

AU - Garcia-Minaur, S.

AU - Lees, M.M.

AU - Ross, A.

AU - Venselaar, H.

AU - Vriend, G.

AU - Takanari, H.

AU - Rook, M.B.

AU - van der Heyden, M.A.

AU - Asselbergs, F.W.

AU - Breur, H.M.

AU - Swinkels, M.E.

AU - Scurr, I.J.

AU - Smithson, S.F.

AU - Knoers, N.V.

AU - van der Smagt, J.J.

AU - Nijman, I.J.

AU - Kloosterman, W.P.

AU - van Haelst, M.M.

AU - van Haaften, G.

AU - Cuppen, E.

N1 - Reporting year: 2012

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

U2 - 10.1038/ng.2324

DO - 10.1038/ng.2324

M3 - Article

SN - 1061-4036

VL - 44

SP - 793

EP - 796

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

Dominant missense mutations in ABCC9 cause Cantu syndrome

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