학술논문
Dominant missense mutations in ABCC9 cause Cantú syndrome.
Document Type
Article
Author
Harakalova, Magdalena; van Harssel, Jeske J T; Terhal, Paulien A; van Lieshout, Stef; Duran, Karen; Renkens, Ivo; Amor, David J; Wilson, Louise C; Kirk, Edwin P; Turner, Claire L S; Shears, Debbie; Garcia-Minaur, Sixto; Lees, Melissa M; Ross, Alison; Venselaar, Hanka; Vriend, Gert; Takanari, Hiroki; Rook, Martin B; van der Heyden, Marcel A G; Asselbergs, Folkert W
Source
Subject
*MISSENSE mutation
*HYPERTRICHOSIS
*ACHONDROPLASIA
*HEART abnormalities
*ELECTROPHYSIOLOGY
*POTASSIUM channels
*NUCLEOTIDE sequence
*
*
*
*
*
*
Language
ISSN
1061-4036
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. [ABSTRACT FROM AUTHOR]