Abstract
AbstractMutations in genes encoding KATPchannel 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 inABCC9(c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATPchannels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATPchannels 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 KATPchannelsABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-functionABCC9mutations, reflecting the opposing consequences of KATPloss- versus gain-of-function.
Funder
E-Rare Joint Transnational Cantú Treat program
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Cited by
31 articles.
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