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Series GSE110592 Query DataSets for GSE110592
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
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.
 
Overall design Heterozygous or homozygous mutant hearts were compared to wild-type littermate hearts.
 
Contributor(s) Matkovich SJ, McClenaghan C, Nichols CG
Citation(s) 30089727
Submission date Feb 14, 2018
Last update date Feb 04, 2020
Contact name Scot J Matkovich
E-mail(s) smatkovich@gmail.com
Organization name Washington University School of Medicine
Department Center for Cardiovascular Research
Street address 660 S Euclid Ave, box 8086
City St. Louis
State/province MO
ZIP/Postal code 63110
Country USA
 
Platforms (1)
GPL21493 Illumina HiSeq 3000 (Mus musculus)
Samples (25)
GSM3003851 WT_A478V_5316
GSM3003852 WT_A478V_5354
GSM3003853 WT_A478V_5355
Relations
BioProject PRJNA434080
SRA SRP132855

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE110592_Cantu_mutant_mouse_hearts_HTSeq_count.txt.gz 1.7 Mb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

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