PUBLICATION
ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9
- Authors
- Smeland, M.F., McClenaghan, C., Roessler, H.I., Savelberg, S., Hansen, G.Å.M., Hjellnes, H., Arntzen, K.A., Müller, K.I., Dybesland, A.R., Harter, T., Sala-Rabanal, M., Emfinger, C.H., Huang, Y., Singareddy, S.S., Gunn, J., Wozniak, D.F., Kovacs, A., Massink, M., Tessadori, F., Kamel, S.M., Bakkers, J., Remedi, M.S., Van Ghelue, M., Nichols, C.G., van Haaften, G.
- ID
- ZDB-PUB-191003-4
- Date
- 2019
- Source
- Nature communications 10: 4457 (Journal)
- Registered Authors
- Bakkers, Jeroen
- Keywords
- none
- MeSH Terms
-
- Adenosine Triphosphate/metabolism*
- Adolescent
- Adult
- Amino Acid Sequence
- Animals
- Cardiomegaly/genetics
- Cardiomegaly/metabolism
- Cell Line
- Channelopathies/metabolism*
- Child
- Disease Models, Animal
- Facies
- Female
- Genetic Diseases, X-Linked/genetics
- Genetic Predisposition to Disease/genetics*
- Heart
- Heart Diseases/genetics
- Heart Diseases/metabolism
- Homozygote
- Humans
- Hypertrichosis/genetics
- Hypertrichosis/metabolism
- Intellectual Disability/metabolism*
- Intellectual Disability/parasitology
- Male
- Mediator Complex/metabolism
- Membrane Proteins/metabolism
- Mice
- Muscular Diseases/genetics
- Muscular Diseases/metabolism*
- Mutation*
- Neurodevelopmental Disorders/genetics
- Neurodevelopmental Disorders/metabolism
- Neurodevelopmental Disorders/physiopathology
- Osteochondrodysplasias/genetics
- Osteochondrodysplasias/metabolism
- Pedigree
- Phenotype
- Rubidium
- Sulfonylurea Receptors/genetics*
- Sulfonylurea Receptors/metabolism*
- Whole Genome Sequencing
- Young Adult
- Zebrafish
- PubMed
- 31575858 Full text @ Nat. Commun.
Citation
Smeland, M.F., McClenaghan, C., Roessler, H.I., Savelberg, S., Hansen, G.Å.M., Hjellnes, H., Arntzen, K.A., Müller, K.I., Dybesland, A.R., Harter, T., Sala-Rabanal, M., Emfinger, C.H., Huang, Y., Singareddy, S.S., Gunn, J., Wozniak, D.F., Kovacs, A., Massink, M., Tessadori, F., Kamel, S.M., Bakkers, J., Remedi, M.S., Van Ghelue, M., Nichols, C.G., van Haaften, G. (2019) ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9. Nature communications. 10:4457.
Abstract
Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú 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 Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping