Dominant missense mutations in ABCC9 cause Cantú syndrome
Copyright policy )Dominant missense mutations in ABCC9 cause Cantú syndrome
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.
- Utrecht University Netherlands
- Royal Netherlands Academy of Arts and Sciences (KNAW) Netherlands
- Royal Netherlands Academy of Arts and Sciences Netherlands
- Radboud University Nijmegen Netherlands
- St. Michael's GAA, Sligo
Adult, Male, Protein Structure, Potassium Channels, Bioinformatics, ATP-Binding Cassette Transporters/genetics, Hypertrichosis, Mutation, Missense, Cardiomegaly, NCMLS 6: Genetics and epigenetic pathways of disease, Tertiary/genetics, Sulfonylurea Receptors, Osteochondrodysplasias, Cell Line, Young Adult, KATP Channels, Receptors, Humans, Exome, Genetic Predisposition to Disease, Potassium Channels, Inwardly Rectifying, Preschool, Child, KATP Channels/genetics, Cell Line, Transformed, Inwardly Rectifying/genetics, Osteochondrodysplasias/genetics, Infant, Newborn, Infant, Genetic Diseases, X-Linked, Newborn, Cardiomegaly/genetics, X-Linked/genetics, HEK293 Cells, Transformed, Drug/genetics, Genetic Diseases, Hypertrichosis/genetics, Child, Preschool, Mutation, NCMLS 7: Chemical and physical biology, ATP-Binding Cassette Transporters, Female, Missense
Adult, Male, Protein Structure, Potassium Channels, Bioinformatics, ATP-Binding Cassette Transporters/genetics, Hypertrichosis, Mutation, Missense, Cardiomegaly, NCMLS 6: Genetics and epigenetic pathways of disease, Tertiary/genetics, Sulfonylurea Receptors, Osteochondrodysplasias, Cell Line, Young Adult, KATP Channels, Receptors, Humans, Exome, Genetic Predisposition to Disease, Potassium Channels, Inwardly Rectifying, Preschool, Child, KATP Channels/genetics, Cell Line, Transformed, Inwardly Rectifying/genetics, Osteochondrodysplasias/genetics, Infant, Newborn, Infant, Genetic Diseases, X-Linked, Newborn, Cardiomegaly/genetics, X-Linked/genetics, HEK293 Cells, Transformed, Drug/genetics, Genetic Diseases, Hypertrichosis/genetics, Child, Preschool, Mutation, NCMLS 7: Chemical and physical biology, ATP-Binding Cassette Transporters, Female, Missense
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).179 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!