Journal Article

ABCC9-related Intellectual disability Myopathy Syndrome is a K ATP channelopathy with loss-of-function mutations in ABCC9

Tessadori, Federico, Gunn, Jamie, van Haaften, Gijs, Kamel, Sarah M, Huang, Yan, Arntzen, Kjell Arne, Van Ghelue, Marijke, Emfinger, Chris H, Wozniak, David F, Hjellnes, Helene, Massink, Maarten, Smeland, Marie F, Harter, Theresa, Remedi, Maria S, Nichols, Colin G, Roessler, Helen I, Kovacs, Attila, McClenaghan, Conor, Savelberg, Sanne, Müller, Kai Ivar, Bakkers, Jeroen, Hansen, Geir Åsmund Myge, Dybesland, Andreas Rosenberger, Sala-Rabanal, Monica, Singareddy, Soma S

2019

Overview

Mutations in genes encoding K 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 K channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional K 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 K 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 K loss- versus gain-of-function.

• Subject: 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