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 KamelJeroen Bakkers, Maria S Remedi, Marijke Van Ghelue, Colin G Nichols, Gijs van Haaften

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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 languageEnglish
Pages (from-to)4457
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 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

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