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

Marie F. Smeland (), Conor McClenaghan, Helen I. Roessler, Sanne Savelberg, Geir Åsmund Myge Hansen, Helene Hjellnes, Kjell Arne Arntzen, Kai Ivar Müller, Andreas Rosenberger Dybesland, Theresa Harter, Monica Sala-Rabanal, Chris H. Emfinger, Yan Huang, Soma S. Singareddy, Jamie Gunn, David F. Wozniak, Attila Kovacs, Maarten Massink, Federico Tessadori, Sarah M. Kamel, Jeroen Bakkers, Maria S. Remedi, Marijke Van Ghelue, Colin G. Nichols and Gijs Haaften ()
Additional contact information
Marie F. Smeland: University Hospital of North Norway
Conor McClenaghan: Washington University
Helen I. Roessler: University Medical Center Utrecht
Sanne Savelberg: University Medical Center Utrecht
Geir Åsmund Myge Hansen: University Hospital of North Norway
Helene Hjellnes: University Hospital of North Norway
Kjell Arne Arntzen: University Hospital of North Norway
Kai Ivar Müller: University Hospital of North Norway
Andreas Rosenberger Dybesland: University Hospital of North Norway
Theresa Harter: Washington University
Monica Sala-Rabanal: Washington University
Chris H. Emfinger: Washington University
Yan Huang: Washington University
Soma S. Singareddy: Washington University
Jamie Gunn: Washington University School of Medicine
David F. Wozniak: Washington University School of Medicine
Attila Kovacs: Washington University School of Medicine
Maarten Massink: University Medical Center Utrecht
Federico Tessadori: University Medical Center Utrecht
Sarah M. Kamel: Hubrecht Institute-KNAW and UMC Utrecht
Jeroen Bakkers: Hubrecht Institute-KNAW and UMC Utrecht
Maria S. Remedi: Washington University
Marijke Van Ghelue: University Hospital of North Norway
Colin G. Nichols: Washington University
Gijs Haaften: University Medical Center Utrecht

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12428-7

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