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| Status |
Public on Feb 04, 2020 |
| Title |
Cardiovascular consequences of K(ATP) dysfunction in Cantu Syndrome arising from in mutations Kir6.1 (KCNJ8) and SUR2 (ABCC9) |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Cantu Syndrome (CS) is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) K(ATP) channel subunits. We generated mice carrying CS-associated SUR2[A478V] and Kir6.1[V65M] mutations, knocked in to the endogenous loci using CRISPR/Cas9 engineering. Mirroring human CS, both of these animals have low systemic blood pressure and dilated, compliant blood vessels, as well as dramatically enlarged hearts with increased contractility. Whole-cell patch-clamp recording reveal enhanced basal K(ATP) conductance in vascular smooth muscle, explaining vasodilation and lower blood pressure. Echocardiography confirms in situ cardiac enlargement, with increased contractility and maintained ejection fraction. Whole-cell voltage clamp of ventricular myocytes reveals increased basal L-type Ca2+ current (LTCC), explaining enhanced contractility. Cardiac hypertrophy and enhanced contractility may arise as secondary compensation, to maintain tissue perfusion in the presence of marked vascular dilation. All of the above features are more prominent in Kir6.1[V65M] animals than in SUR2[A478V] animals, and exacerbated in homozygous animals of each genotype. Compensatory mechanisms are likely to be limiting, since survival is inversely correlated with severity of the phenotype, with very early death in homozygous Kir6.1[V65M] animals. The SUR2[A478V] and Kir6.1[V65M] animals reiterate and explain cardiovascular features in human CS, and raise concerns regarding the long-term consequences of CS specifically, and reduced smooth muscle tone in general.
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| Overall design |
Heterozygous or homozygous mutant hearts were compared to wild-type littermate hearts.
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| Contributor(s) |
Matkovich SJ, McClenaghan C, Nichols CG |
| Citation(s) |
30089727 |
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| Submission date |
Feb 14, 2018 |
| Last update date |
Feb 04, 2020 |
| Contact name |
Scot J Matkovich |
| E-mail(s) |
sjmatkovich@lilly.com
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| Organization name |
Eli Lilly and Company
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| Street address |
Lilly Corporate Center
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| City |
Indianapolis |
| State/province |
IN |
| ZIP/Postal code |
46285 |
| Country |
USA |
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| Platforms (1) |
| GPL21493 |
Illumina HiSeq 3000 (Mus musculus) |
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| Samples (25)
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| Relations |
| BioProject |
PRJNA434080 |
| SRA |
SRP132855 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE110592_Cantu_mutant_mouse_hearts_HTSeq_count.txt.gz |
1.7 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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