@article{f7badca972c643158c942f3ff33ccd73,
title = "ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9",
abstract = "Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cant{\'u} syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cant{\'u} syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.",
keywords = "Adenosine Triphosphate/metabolism, Adolescent, Adult, Amino Acid Sequence, Animals, Cardiomegaly/genetics, Cell Line, Channelopathies/metabolism, Child, Disease Models, Animal, Facies, Female, Genetic Diseases, X-Linked/genetics, Genetic Predisposition to Disease/genetics, Heart, Heart Diseases/genetics, Homozygote, Humans, Hypertrichosis/genetics, Intellectual Disability/metabolism, Male, Mediator Complex/metabolism, Membrane Proteins/metabolism, Mice, Muscular Diseases/genetics, Mutation, Neurodevelopmental Disorders/genetics, Osteochondrodysplasias/genetics, Pedigree, Phenotype, Rubidium, Sulfonylurea Receptors/genetics, Whole Genome Sequencing, Young Adult, Zebrafish",
author = "Smeland, {Marie F} and Conor McClenaghan and Roessler, {Helen I} and Sanne Savelberg and Hansen, {Geir {\AA}smund Myge} and Helene Hjellnes and Arntzen, {Kjell Arne} and M{\"u}ller, {Kai Ivar} and Dybesland, {Andreas Rosenberger} and Theresa Harter and Monica Sala-Rabanal and Emfinger, {Chris H} and Yan Huang and Singareddy, {Soma S} and Jamie Gunn and Wozniak, {David F} and Attila Kovacs and Maarten Massink and Federico Tessadori and Kamel, {Sarah M} and Jeroen Bakkers and Remedi, {Maria S} and {Van Ghelue}, Marijke and Nichols, {Colin G} and {van Haaften}, Gijs",
year = "2019",
month = oct
day = "1",
doi = "10.1038/s41467-019-12428-7",
language = "English",
volume = "10",
pages = "4457",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}