In:
Nature Communications, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2019-10-01)
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 ABCC9 (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 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 K ATP loss- versus gain-of-function.
Type of Medium:
Online Resource
ISSN:
2041-1723
DOI:
10.1038/s41467-019-12428-7
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2019
detail.hit.zdb_id:
2553671-0
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