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

Abstract

Mutations in genes encoding K_ATP 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 <i>ABCC9</i> (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of K_ATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional K_ATP 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_ATP channels <i>ABCC9</i>-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function <i>ABCC9</i> mutations, reflecting the opposing consequences of K_ATP loss- versus gain-of-function.