Congenital Sodium Diarrhea

Janecke, Andreas; Heinz‐Erian, Peter; Müller, Thomas

doi:10.1097/mpg.0000000000001139

Cited by 55 publications

(53 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…More recent genomic studies revised the idea of reduced NHE3 activity as a contributor to the classic or nonsyndromic form of CSD. Using a cohort of 18 patients from 16 families, Janecke et al detected a variety of mutations (point, missense, and truncation) in the NHE3-encoding SLC9A3 gene in half of the studied CSD cases (131). The identified SLC9A3 mutations included one whole-gene deletion, one splicing, and two frameshift mutations, all of which were expected to have abolished NHE3 protein production.…”

Section: Na+/h+ Exchange In Pathological Statesmentioning

confidence: 99%

“…The identified SLC9A3 mutations included one whole-gene deletion, one splicing, and two frameshift mutations, all of which were expected to have abolished NHE3 protein production. Four missense mutations/variants, p.Arg382Gln, p.Ala311Val, p.Ala269Thr, and p.Ala127Thr, were tested in vitro , and all but p.Ala127Thr (benign variant) conferred decreased basal Na + /H + exchange activity (131). In a recent genome-wide SNP analysis of syndromic CSD patients, Heinz-Erian et al identified loss-of function mutations in SPINT2 gene encoding a Kunitz-type serine-protease inhibitor (118).…”

Section: Na+/h+ Exchange In Pathological Statesmentioning

confidence: 99%

See 1 more Smart Citation

SLC9 Gene Family: Function, Expression, and Regulation

Kiela

2018

Comprehensive Physiology

View full text Add to dashboard Cite

The Slc9 family of Na /H exchangers (NHEs) plays a critical role in electroneutral exchange of Na and H in the mammalian intestine as well as other absorptive and secretory epithelia of digestive organs. These transport proteins contribute to the transepithelial Na and water absorption, intracellular pH and cellular volume regulation as well as the electrolyte, acid-base, and fluid volume homeostasis at the systemic level. They also influence the function of other membrane transport mechanisms, affect cellular proliferation and apoptosis as well as cell migration, adherence to the extracellular matrix, and tissue repair. Additionally, they modulate the extracellular milieu to facilitate other nutrient absorption and to regulate the intestinal microbial microenvironment. Na /H exchange is inhibited in selected gastrointestinal diseases, either by intrinsic factors (e.g., bile acids, inflammatory mediators) or infectious agents and associated bacterial toxins. Disrupted NHE activity may contribute not only to local and systemic electrolyte imbalance but also to the disease severity via multiple mechanisms. In this review, we describe the cation proton antiporter superfamily of Na /H exchangers with a particular emphasis on the eight SLC9A isoforms found in the digestive tract, followed by a more integrative description in their roles in each of the digestive organs. We discuss regulatory mechanisms that determine the function of Na /H exchangers as pertinent to the digestive tract, their regulation in pathological states of the digestive organs, and reciprocally, the contribution of dysregulated Na /H exchange to the disease pathogenesis and progression. © 2018 American Physiological Society. Compr Physiol 8:555-583, 2018.

show abstract

Section: Na+/h+ Exchange In Pathological Statesmentioning

confidence: 99%

Section: Na+/h+ Exchange In Pathological Statesmentioning

confidence: 99%

SLC9 Gene Family: Function, Expression, and Regulation

Kiela

2018

Comprehensive Physiology

View full text Add to dashboard Cite

show abstract

“…To date, there have been fewer than 50 CSD cases reported in the literature 45 . Before birth, polyhydroamnios (an excess of amniotic fluid in the amniotic sac) is observed, which is suggestive of an increase in colonic output by the fetus.…”

Section: Intestinal Na+/h+ Exchange In Diarrheal Diseasesmentioning

confidence: 99%

“…Before birth, polyhydroamnios (an excess of amniotic fluid in the amniotic sac) is observed, which is suggestive of an increase in colonic output by the fetus. After birth the disease is characterized by the secretion of a large volume of persistent high Na + diarrhea, often mistaken for urine, which leads to irritability, dehydration, and metabolic acidosis 45 . Although profuse diarrhea continues, electrolyte replacement therapy promotes normal growth and development 46 …”

Section: Intestinal Na+/h+ Exchange In Diarrheal Diseasesmentioning

confidence: 99%

“…These affect approximately a third of CSD patients, are referred to as the syndromic CSD form , and have been linked to a mutation in SPINT2 48 . The classic or nonsyndromic form of CSD is linked strongly to defective NHE activity, and, recently, using a cohort of 18 patients from 16 families, Janecke et al 45 determined that a variety of mutations (point, missense, and truncation) in the NHE3-encoding SLC9A3 gene occurred in a subset (9 of 18) of the studied CSD cases. The identified SLC9A3 mutations included 1 whole-gene deletion, 1 splicing, and 2 frame-shift mutations, all of which were expected to abolish protein production.…”

Section: Intestinal Na+/h+ Exchange In Diarrheal Diseasesmentioning

confidence: 99%

See 1 more Smart Citation

Pathophysiology of Intestinal Na+/H+ Exchange

Gurney

Laubitz

Ghishan

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

View full text Add to dashboard Cite

Several members of the SLC9A family of Na+/H+ exchangers are expressed in the gut, with varying expression patterns and cellular localization. Not only do they participate in the regulation of basic epithelial cell functions, including control of transepithelial Na+ absorption, intracellular pH (pHi), cell volume, and nutrient absorption, but also in cellular proliferation, migration, and apoptosis. Additionally, they modulate the extracellular milieu in order to facilitate other nutrient absorption and to regulate the intestinal microbial microenvironment. Na+/H+ exchangers are frequent targets of inhibition in gastrointestinal pathologies, either by intrinsic factors (e.g. bile acids, inflammatory mediators) or infectious agents and associated microbial toxins. Based on emerging evidence, disruption of NHE activity via impaired expression or function of respective isoforms may contribute not only to local and systemic electrolyte imbalance, but also to the disease severity via multiple mechanisms. Here, we review the current state of knowledge about the roles Na+/H+ exchangers play in the pathogenesis of disorders of diverse origin and affecting a range of GI tissues.

show abstract

Physiology of Electrolyte Transport in the Gut: Implications for Disease

Rao

2019

Comprehensive Physiology

View full text Add to dashboard Cite

We now have an increased understanding of the genetics, cell biology, and physiology of electrolyte transport processes in the mammalian intestine, due to the availability of sophisticated methodologies ranging from genome wide association studies to CRISPR‐CAS technology, stem cell‐derived organoids, 3D microscopy, electron cryomicroscopy, single cell RNA sequencing, transgenic methodologies, and tools to manipulate cellular processes at a molecular level. This knowledge has simultaneously underscored the complexity of biological systems and the interdependence of multiple regulatory systems. In addition to the plethora of mammalian neurohumoral factors and their cross talk, advances in pyrosequencing and metagenomic analyses have highlighted the relevance of the microbiome to intestinal regulation. This article provides an overview of our current understanding of electrolyte transport processes in the small and large intestine, their regulation in health and how dysregulation at multiple levels can result in disease. Intestinal electrolyte transport is a balance of ion secretory and ion absorptive processes, all exquisitely dependent on the basolateral Na + /K + ATPase; when this balance goes awry, it can result in diarrhea or in constipation. The key transporters involved in secretion are the apical membrane Cl − channels and the basolateral Na + ‐K + ‐2Cl − cotransporter, NKCC1 and K + channels. Absorption chiefly involves apical membrane Na + /H + exchangers and Cl − /HCO 3 − exchangers in the small intestine and proximal colon and Na + channels in the distal colon. Key examples of our current understanding of infectious, inflammatory, and genetic diarrheal diseases and of constipation are provided. © 2019 American Physiological Society. Compr Physiol 9:947‐1023, 2019.

show abstract

Congenital Sodium Diarrhea

Cited by 55 publications

References 49 publications

SLC9 Gene Family: Function, Expression, and Regulation

SLC9 Gene Family: Function, Expression, and Regulation

Pathophysiology of Intestinal Na+/H+ Exchange

Physiology of Electrolyte Transport in the Gut: Implications for Disease

Contact Info

Product

Resources

About