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

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)4457
TijdschriftNature Communications
Volume10
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - 01 okt 2019

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