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

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.

Pathophysiological Consequences of KATP Channel Overactivity and Pharmacological Response to Glibenclamide in Skeletal Muscle of a Murine Model of Cantù Syndrome

“…Interestingly, there does not appear to be any obvious skeletal muscle defect, although Albaqumi et al (2014) described a family with congenital hyperinsulinism and rhabdomyolysis associated with Kir6.2 mutations (Albaqumi et al, 2014), and Flanagan et al (2017) recently reported a patient with persistent hyperinsulinaemic hypoglycaemia and severe hypotonia resulting from an activating mutation in a calcium channel subunit, which etiologically may have the same basis (Flanagan et al, 2017). Recently, we described a novel ABCC9-related Intellectual disability Myopathy Syndrome (AIMS) resulting from loss-offunction mutations in ABCC9 (SUR2) (Smeland et al, 2019), in which patients also exhibit muscular pain and fatigue, and evidence of muscle fiber damage.…”

Kir6.1‐dependent KATP channels in lymphatic smooth muscle and vessel dysfunction in mice with Kir6.1 gain‐of‐function

“…Briefly, an indel mutation in ABCC9 (c.3446_3450delACTTCinsGA) resulting in introduction of a premature stop codon (p.Y1148Stop) was generated using CRISPR/Cas9‐mediated genome engineering (Smeland et al . 2019). Heterozygous SUR2 wt/Stop mice were intercrossed to generate homozygous SUR2 Stop/Stop (referred to as SUR2[STOP]) and wild‐type littermates, which were used for experiments.…”

Complex consequences of Cantu syndrome SUR2 variant R1154Q in genetically modified mice

“…Nevertheless, the finding that R1154Q induces such splicing in any genome illustrates the principle that SUR2 GOF mutations can also be associated with additional LOF resulting from variable splicing that leads to reduced protein levels, such that the net effect could be either GOF or LOF in different tissues. We have demonstrated that isolated SUR2 LOF results in a very distinct constellation of features in ABCC9-related intellectual myopathy syndrome (AIMS) ( 49 ). Hence, dual GOF/LOF consequences of CS mutations could result in not just quantitatively, but qualitatively variable outcomes and marked variability of CS pathologies, and hence might underlie the marked variation in severity of CS consequences that is seen in patients ( 24 ).…”