Differential expression of pancreatic protein and chemosensing receptor mRNAs in NKCC1-null intestine

Bradford, Emily M.; Vairamani, Kanimozhi; Shull, Gary E.

doi:10.4291/wjgp.v7.i1.138

Cited by 2 publications

(3 citation statements)

References 45 publications

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“…The patient does not suffer from the inner ear deficit that characterizes the homozygous NKCC1 knockout mouse (Delpire et al 1999; Dixon et al 1999; Flagella et al 1999), but she demonstrates the low blood pressure and gastrointestinal function deficits reminiscent of the null mice (Flagella et al 1999; Wouters et al 2006; Garg et al 2007). In fact, the common gastrointestinal deficit is interesting in light of a recent report showing up-regulation of digestive enzymes produced by the exocrine pancreas of the NKCC1 knockout mouse, possibly as a way to compensate for reduced intestinal function (Bradford et al 2016). …”

Section: Discussionmentioning

confidence: 99%

“…NKCC1, like its family of transporters, plays a role in epithelial ion transport (O'Mahony et al 2008; Bouyer et al 2013; Kidokoro et al 2014; Wei et al 2015), modulates inhibitory synaptic transmission (Sung et al 2000; Dzhala et al 2005), and maintains and regulates cell volume (Wu et al 1998; Bush et al 2010; Mathieu et al 2015). Accordingly, the knockout mouse exhibits multiple phenotypes that include sensorineural deafness (Delpire et al 1999; Dixon et al 1999; Flagella et al 1999), male infertility (Pace et al 2000), intestinal transit deficiency (Flagella et al 1999; Wouters et al 2006; Bradford et al 2016), deficit in saliva secretion (Evans et al 2000), and a pain perception phenotype (Sung et al 2000; Laird et al 2004; Granados-Soto et al 2005). The absence of any report of human mutations in NKCC1 is puzzling and could indicate either complete intolerance to genetic variations (individuals selected out during gestation) or a large tolerance to genetic variations (many individuals carrying mutations without significant deleterious phenotypes).…”

Section: Introductionmentioning

confidence: 99%

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A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1

Delpire

Wolfe

Flores

et al. 2016

Cold Spring Harb Mol Case Stud

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This study describes a 13-yr-old girl with orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, pancreatic insufficiency, and multiorgan failure involving the gut and bladder. Exome sequencing revealed a de novo, loss-of-function allele in SLC12A2, the gene encoding the Na-K-2Cl cotransporter-1. The 11-bp deletion in exon 22 results in frameshift (p.Val1026Phefs*2) and truncation of the carboxy-terminal tail of the cotransporter. Preliminary studies in heterologous expression systems demonstrate that the mutation leads to a nonfunctional transporter, which is expressed and trafficked to the plasma membrane alongside wild-type NKCC1. The truncated protein, visible at higher molecular sizes, indicates either enhanced dimerization or misfolded aggregate. No significant dominant-negative effect was observed. K+ transport experiments performed in fibroblasts from the patient showed reduced total and NKCC1-mediated K+ influx. The absence of a bumetanide effect on K+ influx in patient fibroblasts only under hypertonic conditions suggests a deficit in NKCC1 regulation. We propose that disruption in NKCC1 function might affect sensory afferents and/or smooth muscle cells, as their functions depend on NKCC1 creating a Cl− gradient across the plasma membrane. This Cl− gradient allows the γ-aminobutyric acid (GABA) receptor or other Cl− channels to depolarize the membrane affecting processes such as neurotransmission or cell contraction. Under this hypothesis, disrupted sensory and smooth muscle function in a diverse set of tissues could explain the patient's phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1

Delpire

Wolfe

Flores

et al. 2016

Cold Spring Harb Mol Case Stud

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“…For Gene Ontology (GO) analyses, we used the GOrilla program[ 24 ] ( ). As discussed previously[ 7 , 25 ], two analysis options are available: (1) Two Unranked Lists, in which a target list of genes with a specific range of P values is compared against the list of all genes analyzed; and (2) a Single Rank List, with the entire gene set ranked according to P values, thereby avoiding the use of an arbitrary cutoff of P values. Both analyses were performed.…”

Section: Methodsmentioning

confidence: 99%

NBCe1 Na⁺-HCO3^- cotransporter ablation causes reduced apoptosis following cardiac ischemia-reperfusion injury in vivo

Vairamani

Prasad

Wang

et al. 2018

WJC

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AIMTo investigate the hypothesis that cardiomyocyte-specific loss of the electrogenic NBCe1 Na+-HCO3- cotransporter is cardioprotective during in vivo ischemia-reperfusion (IR) injury.METHODSAn NBCe1 (Slc4a4 gene) conditional knockout mouse (KO) model was prepared by gene targeting. Cardiovascular performance of wildtype (WT) and cardiac-specific NBCe1 KO mice was analyzed by intraventricular pressure measurements, and changes in cardiac gene expression were determined by RNA Seq analysis. Response to in vivo IR injury was analyzed after 30 min occlusion of the left anterior descending artery followed by 3 h of reperfusion.RESULTSLoss of NBCe1 in cardiac myocytes did not impair cardiac contractility or relaxation under basal conditions or in response to β-adrenergic stimulation, and caused only limited changes in gene expression patterns, such as those for electrical excitability. However, following ischemia and reperfusion, KO heart sections exhibited significantly fewer apoptotic nuclei than WT sections.CONCLUSIONThese studies indicate that cardiac-specific loss of NBCe1 does not impair cardiovascular performance, causes only minimal changes in gene expression patterns, and protects against IR injury in vivo .

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Differential expression of pancreatic protein and chemosensing receptor mRNAs in NKCC1-null intestine

Cited by 2 publications

References 45 publications

A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1

A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1

NBCe1 Na⁺-HCO3^- cotransporter ablation causes reduced apoptosis following cardiac ischemia-reperfusion injury in vivo

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Differential expression of pancreatic protein and chemosensing receptor mRNAs in NKCC1-null intestine

Cited by 2 publications

References 45 publications

A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1

A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1

NBCe1 Na+-HCO3- cotransporter ablation causes reduced apoptosis following cardiac ischemia-reperfusion injury in vivo

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NBCe1 Na⁺-HCO3^- cotransporter ablation causes reduced apoptosis following cardiac ischemia-reperfusion injury in vivo