Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea

Janecke, Andreas; Heinz‐Erian, Peter; Yin, Jianyi; Petersen, Britt Sabina; Franke, André; Lechner, Silvia; Fuchs, Irene; Mélancon, Serge B.; Uhlig, Holm H.; Travis, Simon; Marinier, Evelyne; Perisic, Vojislav N.; Ristic, Nina; Gerner, Patrick; Booth, I W; Wedenoja, Satu; Baumgartner, Nadja; Vodopiutz, Julia; Frechette-Duval, Marie Christine; Lafollie, Jan De; Persad, Rabin; Warner, Neil; Tse, Chung Ming; Sud, Karan; Zachos, Nicholas C.; Sarker, Rafiquel; Zhu, Xingen; Muise, Aleixo M.; Zimmer, Klaus Peter; Witt, Heiko; Zoller, Heinz; Donowitz, Mark; Müller, Thomas

doi:10.1093/hmg/ddv367

Cited by 116 publications

(103 citation statements)

References 38 publications

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“…Mutations in the DRA gene lead to congenital chloride diarrhea (24) and defective Cl Ϫ /HCO Ϫ exchange functions on the BBM of villus enterocytes (37). Impaired Na ϩ absorption due to the reduced functional activity of NHE3 is the underlying cause of congenital sodium diarrhea (28). Reduction in the surface area of the small intestine due to the villus atrophy and loss of MVs can further account for the absorptive loss (45) in MVID.…”

Section: Discussionmentioning

confidence: 99%

Identification of intestinal ion transport defects in microvillus inclusion disease

Kravtsov

Ahsan

Kumari

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Loss of function mutations in the actin motor myosin Vb (Myo5b) lead to microvillus inclusion disease (MVID) and death in newborns and children. MVID results in secretory diarrhea, brush border (BB) defects, villus atrophy, and microvillus inclusions (MVIs) in enterocytes. How loss of Myo5b results in increased stool loss of chloride (Cl Ϫ ) and sodium (Na ϩ ) is unknown. The present study used Myo5b loss-of-function human MVID intestine, polarized intestinal cell models of secretory crypt (T84) and villus resembling (CaCo2BBe, C2BBe) enterocytes lacking Myo5b in conjunction with immunofluorescence confocal stimulated emission depletion (gSTED) imaging, immunohistochemical staining, transmission electron microscopy, shRNA silencing, immunoblots, and electrophysiological approaches to examine the distribution, expression, and function of the major BB ion transporters NHE3 (Na ϩ ), CFTR (Cl Ϫ ), and SLC26A3 (DRA) (Cl Ϫ /HCO3 Ϫ ) that control intestinal fluid transport. We hypothesized that enterocyte maturation defects lead villus atrophy with immature secretory cryptlike enterocytes in the MVID epithelium. We investigated the role of Myo5b in enterocyte maturation. NHE3 and DRA localization and function were markedly reduced on the BB membrane of human MVID enterocytes and Myo5bKD C2BBe cells, while CFTR localization was preserved. Forskolin-stimulated CFTR ion transport in Myo5bKD T84 cells resembled that of control. Loss of Myo5b led to YAP1 nuclear retention, retarded enterocyte maturation, and a cryptlike phenotype. We conclude that preservation of functional CFTR in immature enterocytes, reduced functional expression of NHE3, and DRA contribute to Cl Ϫ and Na ϩ stool loss in MVID diarrhea.CFTR; brush border; MVI; Myo5b; NHE3; MVID MICROVILLUS INCLUSION DISEASE (MVID) is a rare but life-threatening disease that affects newborns and children and leads to rapid death from severe secretory diarrhea. MVID clusters in the Middle East and Navajo Indian populations in the US and is associated with consanguinity (41,42,47,51,61). Stool volumes are greater than 125 ml·kg Ϫ1 ·day Ϫ1 with elevated levels of chloride (Cl Ϫ ) and sodium (Na

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Section: Discussionmentioning

confidence: 99%

Identification of intestinal ion transport defects in microvillus inclusion disease

Kravtsov

Ahsan

Kumari

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Classical or non-syndromic CSD results from loss-of-function mutations in the Na/H + exchanger NHE3, which is critical for normal Na + and fluid absorption from the intestine, as well as normal acid-base homeostasis. 37 CSD also results from activating mutations in the guanylin receptor GC-C (GUCY2C), resulting in elevated cellular cyclic guanosine monophosphate levels, inhibition of NHE3 function, and stimulation of chloride secretion via CFTR chloride channels. 50 Lastly, a syndromic form of CSD (SPINT2) that overlaps in phenotype with CTE has been decribed.…”

Section: Disorders Of Epithelial Nutrient/electrolyte Transportmentioning

confidence: 99%

Advances in Evaluation of Chronic Diarrhea in Infants

et al. 2018

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Diarrhea is common in infants (children less than 2 years of age), usually acute, and, if chronic, commonly caused by allergies and occasionally by infectious agents. Congenital diarrheas and enteropathies (CODEs) are rare causes of devastating chronic diarrhea in infants. Evaluation of CODEs is a lengthy process and infrequently leads to a clear diagnosis. However, genomic analyses and the development of model systems have increased our understanding of CODE pathogenesis. With these advances, a new diagnostic approach is needed. We propose a revised approach to determine causes of diarrhea in infants, including CODEs, based on stool analysis, histologic features, responses to dietary modifications, and genetic tests. After exclusion of common causes of diarrhea in infants, the evaluation proceeds through analyses of stool characteristics (watery, fatty, or bloody) and histologic features, such as the villus to crypt ratio in intestinal biopsies. Infants with CODEs resulting from defects in digestion, absorption, transport of nutrients and electrolytes, or enteroendocrine cell development or function have normal villi to crypt ratios; defects in enterocyte structure or immune-mediated conditions result in an abnormal villus to crypt ratios and morphology. Whole-exome and genome sequencing in the early stages of evaluation can reduce the time required for a definitive diagnosis of CODEs, or lead to identification of new variants associated with these enteropathies. The functional effects of gene mutations can be analyzed in model systems such as enteroids or induced pluripotent stem cells and are facilitated by recent advances in gene editing procedures. Characterization and investigation of new CODE disorders will improve management of patients and advance our understanding of epithelial cells and other cells in the intestinal mucosa.

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“…(10,11,25) While it has been shown that diarrhea associated with ulcerative colitis (UC) occurs primarily as the result of inhibition of NHE-mediated Na + absorption in UC, (30) …”

Section: Ibd As a Consequence Of Loss Of Nhe3 Functionmentioning

confidence: 99%

Congenital Sodium Diarrhea

Janecke

Heinz‐Erian

Müller

2016

J. pediatr. gastroenterol. nutr.

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Congenital diarrheal disorders (CDDs) represent a group of challenging clinical conditions for pediatricians because of the severity of the presentation and the broad range of possible differential diagnoses. CDDs arise from alterations in the transport of nutrients and electrolytes across the intestinal mucosa, from enterocyte and enteroendocrine cell differentiation and/or polarization defects, and from the modulation of the intestinal immune response. Advances were made recently in deciphering the etiology and pathophysiology of one of these disorders, congenital sodium diarrhea (CSD). CSD refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. A syndromic form of CSD features choanal and intestinal atresias as well as recurrent corneal erosions. Small bowel histology frequently detects an epithelial "tufting" dysplasia. It is autosomal recessively inherited, and caused by SPINT2 mutations. The nonsyndromic form of CSD can be caused by dominant activating mutations in GUCY2C, encoding intestinal receptor guanylate cyclase C (GC-C), and by autosomal recessive SLC9A3 loss-of-function mutations. SLC9A3 encodes Na/H antiporter 3, the major intestinal brush border Na/H exchanger, and a downstream target of GC-C. A number of patients with GUCY2C and SLC9A3 mutations developed inflammatory bowel disease. Both the number of recognized CDD forms as well as the number of underlying disease genes are gradually increasing. Knowledge of these CDD genes enables noninvasive, next-generation gene panel-based testing to facilitate an early diagnosis in CDD. Primary Na/H antiporter 3 and GC-C malfunction is implicated as a predisposition for inflammatory bowel disease in subset of patients.

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Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea

Cited by 116 publications

References 38 publications

Identification of intestinal ion transport defects in microvillus inclusion disease

Identification of intestinal ion transport defects in microvillus inclusion disease

Advances in Evaluation of Chronic Diarrhea in Infants

Congenital Sodium Diarrhea

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