Abstract
Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits, the most common mutations being SUR2[R1154Q] and SUR2[R1154W], carried by approximately 30% of patients. We used CRISPR/Cas9 genome engineering to introduce the equivalent of the human SUR2[R1154Q] mutation into the mouse ABCC9 gene. Along with minimal CS disease features, R1154Q cardiomyocytes and vascular smooth muscle showed much lower KATP current density and pinacidil activation than WT cells. Almost complete loss of SUR2-dependent protein and KATP in homozygous R1154Q ventricles revealed underlying diazoxide-sensitive SUR1-dependent KATP channel activity. Surprisingly, sequencing of SUR2 cDNA revealed 2 distinct transcripts, one encoding full-length SUR2 protein; and the other with an in-frame deletion of 93 bases (corresponding to 31 amino acids encoded by exon 28) that was present in approximately 40% and approximately 90% of transcripts from hetero- and homozygous R1154Q tissues, respectively. Recombinant expression of SUR2A protein lacking exon 28 resulted in nonfunctional channels. CS tissue from SUR2[R1154Q] mice and human induced pluripotent stem cell–derived (hiPSC-derived) cardiomyocytes showed only full-length SUR2 transcripts, although further studies will be required in order to fully test whether SUR2[R1154Q] or other CS mutations might result in aberrant splicing and variable expressivity of disease features in human CS.
Highlights
Cantu syndrome (CS), which has been referred to as hypertrichosis-osteochondrodysplasia-cardiomegaly syndrome, is a rare multiorgan disease first recognized as such in 1982 [1]
We show that the cardiovascular abnormalities in these CS mice were much less severe than in either of the 2 previously studied animal models, but this was accompanied by a marked decrease in SUR2-dependent Kir6.1 and SUR2 subunits of ATP-sensitive potassium (KATP) density, in both cardiac and smooth muscle cells
Isolated aortic diameter was greater in SUR2WT/RQ than WT mice at all pressures (Figure 1C) again, there was no further increase in SUR2RQ/RQ mice, and carotid artery dimensions were not different between WT and R1154Q animals (Figure 1D)
Summary
Cantu syndrome (CS), which has been referred to as hypertrichosis-osteochondrodysplasia-cardiomegaly syndrome, is a rare multiorgan disease first recognized as such in 1982 [1]. CS is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia, and multiple cardiovascular abnormalities, including cardiomegaly, hypertrophy, pericardial effusion, pulmonary hypertension, and patent ductus arteriosus and cerebrovascular defects [2,3,4,5]. Multiple reports have confirmed that autosomal dominant gain-of-function (GOF) mutations in KCNJ8 and ABCC9, the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (KATP) channels, represent the genetic basis of CS [6,7,8,9,10,11]. KCNJ8 and ABCC9 are adjacent genes on human chromosome 12p12.1. A paralogous pair of genes (KCNJ11 [Kir6.2] and ABCC8 [SUR1]) is located on chromosome 11p15.1, with the result that multiple subunit combinations may exist in KATP channels in different tissues. KATP channels in vascular smooth muscle are predominantly composed of Kir6.1 and SUR2B [20, 21], whereas SUR2A predominates in cardiac ventricular myocyte KATP channels [22, 23]
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