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.
Original language | English |
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Pages (from-to) | 4457 |
Journal | Nature Communications |
Volume | 10 |
Issue number | 1 |
DOIs | |
Publication status | Published - 01 Oct 2019 |
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