Mutations of the Down–regulated in adenoma (DRA) gene cause congenital chloride diarrhoea

Höglund, Pia; Haila, Siru; Socha, Jerzy; Tomaszewski, L; Saarialho–Kere, Ulpu; Karjalainen-Lindsberg, M-L; Airola, Kristiina; Holmberg, Christer; A, de la Chapelle; Kere, Juha

doi:10.1038/ng1196-316

Cited by 379 publications

(345 citation statements)

References 16 publications

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“…In this disorder, high-volume watery diarrhea begins at birth (38,39). The disorder is caused by a loss of function mutation in the downregulated in adenoma (DRA or CLD) gene, leading to an absence of any functioning gut Cl Ϫ /HCO 3 Ϫ exchange (40,41). As a result of the absence of Cl Ϫ absorption and HCO 3 Ϫ secretion, the diarrhea fluid contains primarily Na ϩ , Cl Ϫ , and K ϩ ( (2), but the disorder is sustained unless the Cl Ϫ losses can be replaced (Table 4).…”

Section: Diarrheamentioning

confidence: 99%

Acid-Base Disturbances in Gastrointestinal Disease

Gennari¹,

Weise²

2008

Clinical Journal of the American Society of Nephrology

137

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Disruption of normal gastrointestinal function as a result of infection, hereditary or acquired diseases, or complications of surgical procedures uncovers its important role in acid-base homeostasis. Metabolic acidosis or alkalosis may occur, depending on the nature and volume of the unregulated losses that occur. Investigation into the specific pathophysiology of gastrointestinal disorders has provided important new insights into the normal physiology of ion transport along the gut and has also provided new avenues for treatment. This review provides a brief overview of normal ion transport along the gut and then discusses the pathophysiology and treatment of the metabolic acid-base disorders that occur when normal gut function is disrupted.

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Section: Diarrheamentioning

confidence: 99%

Acid-Base Disturbances in Gastrointestinal Disease

Gennari¹,

Weise²

2008

Clinical Journal of the American Society of Nephrology

137

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“…During passage through the epididymal ducts, the composition of the luminal fluid is further gradually changed by sequential absorption and secretion processes (Turner 2002, Wong et al 2002. Water absorption in efferent ducts is allowed by interdependent transport of Cl K and Na C , which may be mediated by an apical anion Cl hereditary diseases when mutated (Hastbacka et al 1994, Hoglund et al 1996, Everett et al 1997, Toure et al 2001, Liu et al 2003 OMIM database which can be viewed online at www. ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM).…”

Section: Introductionmentioning

confidence: 99%

Expression of ion transport-associated proteins in human efferent and epididymal ducts

Kujala¹,

Hihnala²,

Tienari³

et al. 2007

Reproduction

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Appropriate intraluminal microenvironment in the epididymis is essential for maturation of sperm. To clarify whether the anion transporters SLC26A2, SLC26A6, SLC26A7, and SLC26A8 might participate in generating this proper intraluminal milieu, we studied the localization of these proteins in the human efferent and the epididymal ducts by immunohistochemistry. In addition, immunohistochemistry of several SLC26-interacting proteins was performed: the Na C /H C exchanger 3 (NHE3), the Cl K channel cystic fibrosis transmembrane conductance regulator (CFTR), the proton pump V-ATPase, their regulator Na C /H C exchanger regulating factor 1 (NHERF-1), and carbonic anhydrase II (CAII). Our results show that SLC26A6, CFTR, NHE3, and NHERF-1 are co-expressed on the apical side of the nonciliated cells, and SLC26A2 appears in the cilia of the ciliated cells in the human efferent ducts. In the epididymal ducts, SLC26A6, CFTR, NHERF-1, CAII, and V-ATPase (B and E subunits) were co-localized to the apical mitochondria rich cells, while SLC26A7 was expressed in a subgroup of basal cells. SLC26A8 was not found in the structures studied. This is the first study describing the localization of SLC26A2, A6 and A7, and NHERF-1 in the efferent and the epididymal ducts. Immunolocalization of human CFTR, NHE3, CAII, and V-ATPase in these structures differs partly from previous reports from rodents. Our findings suggest roles for these proteins in male fertility, either independently or through interaction and reciprocal regulation with co-localized proteins shown to affect fertility, when disrupted. Reproduction (2007) 133 775-784

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“…The chloride/bicarbonate exchanger SLC26A2/ down-regulated in adenoma is expressed in the gastrointestinal tract, and mutations in this gene cause congenital chloride diarrhea (15,16). SLC26A3/diastrophic dysplasia sulfate transporter is a sulfate transporter predominantly expressed in cartilage, and recessive alterations in this gene are the molecular basis of several forms of chondrodysplasias (17)(18)(19)).…”

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confidence: 99%

Functional Characterization of Pendrin in a Polarized Cell System

Gillam

Sidhaye

Lee

et al. 2004

Journal of Biological Chemistry

142

110

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Pendred's syndrome is an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the PDS/SLC26A4 gene that encodes pendrin. Functionally, pendrin is a transporter of chloride and iodide in Xenopus oocytes and heterologous mammalian cells and a chloride/base exchanger in ␤-intercalated cells of the renal cortical collecting duct. The partially impaired thyroidal iodide organification in Pendred's syndrome suggests a possible role of pendrin in iodide transport at the apical membrane of thyroid follicular cells, but experimental evidence for this concept is lacking. The iodide transport properties of pendrin were determined in polarized Madin-Darby canine kidney cells expressing the sodium iodide symporter (NIS), pendrin, or NIS and pendrin using a bicameral system-permitting measurement of iodide content in the basal, intracellular, and apical compartments. Moreover, we determined the functional consequences of two naturally occurring mutations (L676Q and FS306>309X). In polarized Madin-Darby canine kidney cells, NIS mediates uptake at the basolateral membrane. Only minimal amounts of iodide reach the apical compartment in the absence of pendrin. In cells expressing NIS and pendrin, pendrin mediates transport of iodide into the apical chamber. Wild type pendrin also mediates iodide efflux in transiently transfected cells. In contrast, both pendrin mutants lose the ability to promote iodide efflux. These results provide evidence that pendrin mediates apical iodide efflux from polarized mammalian cells loaded with iodide. Consistent with the partial organification defect observed in patients with Pendred's syndrome, naturally occurring mutations of pendrin lead to impaired transport of iodide.

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Mutations of the Down–regulated in adenoma (DRA) gene cause congenital chloride diarrhoea

Cited by 379 publications

References 16 publications

Acid-Base Disturbances in Gastrointestinal Disease

Acid-Base Disturbances in Gastrointestinal Disease

Expression of ion transport-associated proteins in human efferent and epididymal ducts

Functional Characterization of Pendrin in a Polarized Cell System

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