Liddle syndrome in a Serbian family and literature review of underlying mutations

Bogdanović, Radovan; Kuburovic, Vladimir; Stajić, Nataša; Mughal, Sadaf S.; Hilger, Alina C.; Ninić, Sanja; Prijić, Sergej; Ludwig, Michael

doi:10.1007/s00431-011-1581-8

Cited by 34 publications

(33 citation statements)

References 47 publications

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“…Liddle syndrome (OMIM #177200) is an autosomal dominant disorder characterized by early-onset hypertension associated with hypokalemia, metabolic alkalosis, and low levels of plasma renin activity (PRA) and aldosterone (Bogdanović et al, 2012; Hansson et al, 1995; Liddle et al, 1963) (see Table 14). The degree of phenotypic expression may vary even within the same family (Bogdanović et al, 2012; Findling et al, 1997).…”

Section: Diseases Associated With Enac Mutationsmentioning

confidence: 99%

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Epithelial sodium channel (ENaC) family: Phylogeny, structure–function, tissue distribution, and associated inherited diseases

Hanukoglu

2016

Gene

337

345

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The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na+ ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na+ in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. In multi-ciliated cells, ENaC is located in cilia and plays an essential role in the regulation of epithelial surface liquid volume necessary for cilial transport of mucus and gametes in the respiratory and reproductive tracts respectively. The subunits that form ENaC (named as alpha, beta, gamma and delta, encoded by genes SCNN1A, SCNN1B, SCNN1G, and SCNN1D) are members of the ENaC/Degenerin superfamily. The earliest appearance of ENaC orthologs is in the genomes of the most ancient vertebrate taxon, Cyclostomata (jawless vertebrates) including lampreys, followed by earliest representatives of Gnathostomata (jawed vertebrates) including cartilaginous sharks. Among Euteleostomi (bony vertebrates), Actinopterygii (ray finned-fishes) branch has lost ENaC genes. Yet, most animals in the Sarcopterygii (lobe-finned fish) branch including Tetrapoda, amphibians and amniotes (lizards, crocodiles, birds, and mammals), have four ENaC paralogs. We compared the sequences of ENaC orthologs from 20 species and established criteria for the identification of ENaC orthologs and paralogs, and their distinction from other members of the ENaC/Degenerin superfamily, especially ASIC family. Differences between ENaCs and ASICs are summarized in view of their physiological functions and tissue distributions. Structural motifs that are conserved throughout vertebrate ENaCs are highlighted. We also present a comparative overview of the genotype-phenotype relationships in inherited diseases associated with ENaC mutations, including multisystem pseudohypoaldosteronism (PHA1B), Liddle syndrome, cystic fibrosis-like disease and essential hypertension.

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Section: Diseases Associated With Enac Mutationsmentioning

confidence: 99%

“…The degree of phenotypic expression may vary even within the same family (Bogdanović et al, 2012; Findling et al, 1997). …”

Section: Diseases Associated With Enac Mutationsmentioning

confidence: 99%

Epithelial sodium channel (ENaC) family: Phylogeny, structure–function, tissue distribution, and associated inherited diseases

Hanukoglu

2016

Gene

337

345

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“…However, we present an early-onset case in a 5-yr-old girl with a p.Arg566* mutation of the epithelial sodium channel β-subunit. Other mutations reported in Liddle syndrome that delete or alter a conserved proline-rich amino acid sequence, PY motif, have been reported in childhood or adolescent cases and include P616L missense mutation in an 8-yr-old Czech boy (Ciechanowicz et al 2005) and a 13-yr-old Serbian boy (Bogdanovic et al 2012) and a Y618H mutation in a 4-yr-old Afro-Haitian girl (Freundlich and Ludwig 2005). …”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome

Polfus

Boerwinkle

Gibbs

et al. 2016

Cold Spring Harb Mol Case Stud

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To comprehensively evaluate a European–American child with severe hypertension, whole-exome sequencing (WES) was performed on the child and parents, which identified causal variation of the proband's early-onset disease. The proband's hypertension was resistant to treatment, requiring a multiple drug regimen including amiloride, spironolactone, and hydrochlorothiazide. We suspected a monogenic form of hypertension because of the persistent hypokalemia with low plasma levels of renin and aldosterone. To address this, we focused on rare functional variants and indels, and performed gene-based tests incorporating linkage scores and allele frequency and filtered on deleterious functional mutations. Drawing upon clinical presentation, 27 genes were selected evidenced to cause monogenic hypertension and matched to the gene-based results. This resulted in the identification of a stop-gain mutation in an epithelial sodium channel (ENaC), SCNN1B, an established Liddle syndrome gene, shared by the child and her father. Interestingly, the father also harbored a missense mutation (p.Trp552Arg) in the α-subunit of the ENaC trimer, SCNN1A, possibly pointing to pseudohypoaldosteronism type I. This case is unique in that we present the early-onset disease and treatment response caused by a canonical stop-gain mutation (p.Arg566*) as well as ENaC digenic hits in the father, emphasizing the utility of WES informing precision medicine.

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“…Mutations in either beta-or gamma-subunit cause an increased channel number and activity of amiloride-sensitive sodium current by several-fold of this type of ENaC receptor [77][78][79][80] . A heterozygous mutation c.C1852(p.Pro618Ser) in the SCNN1B gene was • reported in a Serbian family (son, mother and uncle) in a 13-year-old asymptomatic boy with severe hypertension [ 81 ] . The familial history recollected over four generations seems to be concordant with this pathology.…”

Section: Liddle Syndromementioning

confidence: 97%

Syndromes of Mineralocorticoid Excess

Melcescu

Koch

2012

Endocrine Hypertension

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In addition to obesity, diabetes type 2, and the metabolic syndrome, hypertension represents a major public and global health problem, most of which can be improved by lifestyle changes, including changing dietary habits with less consumption of processed and preserved foods, which generally contain higher amounts of salt than freshly prepared food items. Amongst causes for endocrine hypertension are syndromes of mineralocorticoid excess typically resulting from overactive amiloride-sensitive sodium channels located in the distal convoluted tubules and collecting ducts of the kidney, as well as other tissues, including vascular smooth muscle. The net effect of such an overactivation, which occurs mostly in primary aldosteronism is sodium and water retention with volume expansion and hypertension that is exacerbated by a diet high in salt. Biochemically, plasma renin activity is suppressed and hypokalemia may be present. Aldosterone mediates its action through the mineralocortoid receptor (MR), which regulates salt homeostasis in the kidneys and plays a range of other roles in the vasculature, heart, brain, and adipose tissue.Excessive MR activation can promote in fl ammation, fi brosis, and heart disease as well as psychiatric illness, including anxiety and depression, through key modulators, including the glucocorticoid receptor and the 11 b -hydroxysteroid dehydrogenases.Apart from aldosterone, the MR is also activated by products of abnormal adrenal steroid biosynthesis, dysregulated metabolism of cortisol in cells that are targets of mineralocorticoids, and activating mutations of the MR or of ion channels that are inducible by the MR. We provide here an overview of mineralocorticoid excess caused by congenital adrenal hyperplasia due to mutations of the 11beta-hydroxylase and 17alpha-hydroxylase genes, by mutations of the 11beta-hydroxysteroid dehydrogenase type 2 gene (apparent mineralocorticoid excess (AME)), mutations of the epithelial sodium channel genes (Liddle syndrome), mutations of the

show abstract

Liddle syndrome in a Serbian family and literature review of underlying mutations

Abstract: Liddle syndrome should be considered as a cause of hypertension in children or adolescents particularly with suppressed renin activity. Early diagnosis and appropriately tailored treatment avoid complications of long-term unrecognized or inappropriately managed hypertension.

Cited by 34 publications

References 47 publications

Epithelial sodium channel (ENaC) family: Phylogeny, structure–function, tissue distribution, and associated inherited diseases

Epithelial sodium channel (ENaC) family: Phylogeny, structure–function, tissue distribution, and associated inherited diseases

Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome

Syndromes of Mineralocorticoid Excess

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