Liddle's syndrome associated with a point mutation in the extracellular domain of the epithelial sodium channel γ subunit

Hiltunen, Timo P.; Hannila‐Handelberg, Tuula; Petäjäniemi, Noora; Kantola, Ilkka; Tikkanen, Ilkka; Virtamo, Jarmo; Gautschi, Ivan; Schild, Laurent; Kontula, Kimmo

doi:10.1097/00004872-200212000-00017

Cited by 76 publications

(70 citation statements)

References 24 publications

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“…[98][99][100][101][102] A gain of function mutation has also been described in the extracellular domain of g-ENaC, but no mutations have yet been described in a-ENaC. 103 Recombinant mice expressing ENaC with the same truncating mutation as the initial proband recapitulate the features of the human condition when fed a high salt diet -hypertension, hypokalaemic metabolic alkalosis and evidence of end-organ damage (cardiac hypertrophy). There is also increased Na þ reabsorption in the distal colon suggesting an additional contribution to salt-loading and human hypertension.…”

Section: Disorders Of Enac Functionmentioning

confidence: 99%

The renal channelopathies

Loudon

Fry

2014

Ann Clin Biochem

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Specific channels permit movement of selected ions through cellular membranes, and are of vital importance in a number of physiological processes, particularly in excitable tissues such as nerve and muscle, but also in endocrine organs and in epithelial biology. Disorders of channel proteins are termed channelopathies, and their importance is increasingly recognised within medicine. In the kidney, ion channels have critical roles enabling sodium and potassium reuptake or excretion along the nephron, in magnesium homeostasis, in the control of water reabsorption in the collecting duct, and in determining glomerular permeability. In this review, we assess the channelopathies encountered in each nephron segment, and see how their molecular and genetic characterisation in the past 20-30 years has furthered our understanding of normal kidney physiology and disease processes, aids correct diagnosis and promises future therapeutic opportunities.

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Section: Disorders Of Enac Functionmentioning

confidence: 99%

The renal channelopathies

Loudon

Fry

2014

Ann Clin Biochem

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“…It is clear that not all biological processes are governed by large changes. Indeed, modest changes in expression levels or enzymatic activities have been reported previously to have clear physiological implications, which even may underlie diseases [31,32]. The stabilizing effect of D1 may become important under conditions where the concentration of the ligand is restricted, and the spreading of GDNF in tissues has indeed been shown to be a 'bottleneck' in therapeutic applications [33].…”

Section: Discussionmentioning

confidence: 99%

The first cysteine-rich domain of the receptor GFRα1 stabilizes the binding of GDNF

Virtanen

Yang

Bespalov

et al. 2005

Biochemical Journal

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The GDNF (glial cell line-derived neurotrophic factor)-binding receptor GFRα1 (GDNF family receptor α1) is attached to the membrane by a GPI (glycosylphosphatidylinositol) anchor and consists of three cysteine-rich domains. The region corresponding to the second and third domains has been shown previously to participate in ligand binding, and to interact with the transmembrane tyrosine kinase receptor RET. No function has so far been found for the N-terminal, first domain (D1). Here we show that the GPI-anchored full-length receptor binds 125 I-GDNF two times more tightly than does a GPI-anchored truncated receptor lacking D1. Scintillation proximity assays with purified receptor proteins also show that the GDNF-binding capacity of the soluble fulllength GFRα1 is two times higher than the GDNF-binding capacity of the soluble D1-truncated GFRα1. As RET stabilizes the binding of GDNF equally well to the full-length and truncated receptors, D1 seems not to be involved in the interaction between GFRα1 and RET. Moreover, soluble full-length GFRα1 mediates GDNF-promoted neurite outgrowth in PC6-3 cells more efficiently than the soluble truncated GFRα1 protein. At low concentrations, the soluble fulllength receptor mediates the phosphorylation of RET more efficiently than the soluble truncated receptor. However, when the receptors are overexpressed on the cell surface as GPI-anchored proteins, or added to the growth medium at high concentrations as soluble proteins, full-length and truncated GFRα1 are indistinguishable in GDNF-dependent RET-phosphorylation assays. High levels of the receptors can thus mask a slightly impaired function in the phosphorylation assay. Based on assays with both GPI-anchored and soluble receptors, we therefore conclude that D1 contributes to the optimal function of GFRα1 by stabilizing the interaction between GFRα1 and GDNF.

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“…Combination with a thiazide diuretic (25 mg hydrochlorothiazide daily) normalized the blood pressure. Exon 13 of the SCNN1B and SCNN1G genes encoding the b and g subunits respectively of the epithelial sodium channel were sequenced without evidence of mutations causing Liddle's syndrome (27,28,29). At subsequent follow-up visits during the following 6 years, during which the patient was treated with varying doses of amiloride and hydrochlorothiazide, his blood pressure was somewhat variable and not always desirable (systolic blood pressure (SBP) 114-158 mmHg and diastolic blood pressure (DBP) 75-104 mmHg).…”

Section: Case Reportmentioning

confidence: 99%

Generalized glucocorticoid resistance caused by a novel two-nucleotide deletion in the hormone-binding domain of the glucocorticoid receptor gene NR3C1

Donner

Hiltunen

Jänne

et al. 2013

European Journal of Endocrinology

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Objective: Generalized glucocorticoid resistance is characterized by impaired cortisol signaling, resulting from mutations of the glucocorticoid receptor (GR) gene NR3C1. The objective of our study was to identify the causative mutation in a patient with clinical manifestations compatible with generalized glucocorticoid resistance and to determine the functional consequences of the mutation. The possible occurrence of NR3C1 mutations in a selected group of hypertensive subjects with low plasma renin and aldosterone levels was also explored. Patients: The proband, a male athlete, was diagnosed with hypertension associated with low plasma renin activity and low serum aldosterone concentration at the age of 27 years. Liddle's syndrome was suspected and the patient was treated with amiloride with initial success. Subsequent examinations revealed elevated serum cortisol and ACTH levels, with resistance to suppression with low doses of dexamethasone. After identification of an NR3C1 mutation in the proband, the available family members and 51 nonrelated hypertensive subjects with low plasma renin and aldosterone concentrations were also studied. Results: A two-nucleotide deletion in exon 9a, predicted to cause a frameshift mutation (p.L773VfsX25) in the hormone-binding domain of the GR, was identified in the patient in a heterozygous form. Affected brother and father died of premature coronary heart disease. Functional studies in COS-1 cells showed that this mutation eliminates both ligand-binding and transactivation ability of the receptor. No pathogenic NR3C1 mutations were identified in 51 unrelated hypertensive patients with low plasma renin and aldosterone levels. Conclusion: We identified a novel frameshift mutation in NR3C1 as the cause of glucocorticoid resistance. The mutation eliminates the functional activity of the GR, as studied by in vitro experiments. Mutations in NR3C1 do not seem to be common causes for hypertension with low renin and aldosterone levels.

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Liddle's syndrome associated with a point mutation in the extracellular domain of the epithelial sodium channel γ subunit

Abstract: This study describes the first mutation located in the extracellular domain of an ENaC subunit associated with an increased ENaC activity and Liddle's syndrome.

Cited by 76 publications

References 24 publications

The renal channelopathies

The renal channelopathies

The first cysteine-rich domain of the receptor GFRα1 stabilizes the binding of GDNF

Generalized glucocorticoid resistance caused by a novel two-nucleotide deletion in the hormone-binding domain of the glucocorticoid receptor gene NR3C1

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