TY - JOUR
T1 - Kir6.1- And SUR2-dependent KATP overactivity disrupts intestinal motility in murine models of Cantú syndrome
AU - York, Nathaniel W.
AU - Parker, Helen
AU - Xie, Zili
AU - Tyus, David
AU - Waheed, Maham Akbar
AU - Yan, Zihan
AU - Grange, Dorothy K.
AU - Remedi, Maria Sara
AU - England, Sarah K.
AU - Hu, Hongzhen
AU - Nichols, Colin G.
N1 - Funding Information:
This work was supported by NIH R35 HL140024 to CGN and by NIH T32 HL125241 and DK108742 (fellowship support of NWY).
Publisher Copyright:
© 2020, York et al.
PY - 2020/12/3
Y1 - 2020/12/3
N2 - Cantú syndrome (CS), caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunit genes, is frequently accompanied by gastrointestinal (GI) dysmotility, and we describe 1 CS patient who required an implanted intestinal irrigation system for successful stooling. We used gene-modified mice to assess the underlying KATP channel subunits in gut smooth muscle and to model the consequences of altered KATP channels in CS gut. We show that Kir6.1/SUR2 subunits underlie smooth muscle KATP channels throughout the small intestine and colon. Knockin mice, carrying human KCNJ8 and ABCC9 CS mutations in the endogenous loci, exhibited reduced intrinsic contractility throughout the intestine, resulting in death when weaned onto solid food in the most severely affected animals. Death was avoided by weaning onto a liquid gel diet, implicating intestinal insufficiency and bowel impaction as the underlying cause, and GI transit was normalized by treatment with the KATP inhibitor glibenclamide. We thus define the molecular basis of intestinal KATP channel activity, the mechanism by which overactivity results in GI insufficiency, and a viable approach to therapy.
AB - Cantú syndrome (CS), caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunit genes, is frequently accompanied by gastrointestinal (GI) dysmotility, and we describe 1 CS patient who required an implanted intestinal irrigation system for successful stooling. We used gene-modified mice to assess the underlying KATP channel subunits in gut smooth muscle and to model the consequences of altered KATP channels in CS gut. We show that Kir6.1/SUR2 subunits underlie smooth muscle KATP channels throughout the small intestine and colon. Knockin mice, carrying human KCNJ8 and ABCC9 CS mutations in the endogenous loci, exhibited reduced intrinsic contractility throughout the intestine, resulting in death when weaned onto solid food in the most severely affected animals. Death was avoided by weaning onto a liquid gel diet, implicating intestinal insufficiency and bowel impaction as the underlying cause, and GI transit was normalized by treatment with the KATP inhibitor glibenclamide. We thus define the molecular basis of intestinal KATP channel activity, the mechanism by which overactivity results in GI insufficiency, and a viable approach to therapy.
UR - http://www.scopus.com/inward/record.url?scp=85097312928&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.141443
DO - 10.1172/jci.insight.141443
M3 - Article
C2 - 33170808
AN - SCOPUS:85097312928
SN - 2379-3708
VL - 5
JO - JCI Insight
JF - JCI Insight
IS - 23
M1 - e141443
ER -