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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liddle's syndrome is a rare monogenic form of hypertension caused by truncating or missense mutations in the C termini of the epithelial sodium channel beta- or gamma-subunits. These mutations delete or alter a conserved proline-rich amino acid sequence referred to as the PY-motif. We report here a Liddle's syndrome family with a betaArg564X mutation with a premature stop codon deleting the PY-motif of the beta-subunit. This family shows marked phenotypic variation in blood pressure, serum potassium levels, and age of onset of hypertension. Given the similarity with primary hypertension, changes in the C termini of the beta- or gamma-subunits may contribute to the development of primary hypertension or to hypertension associated with diabetic nephropathy. Accordingly, the coding sequences for the cytoplasmic C termini of the beta- and gamma-subunits were screened for mutations with the use of polymerase chain reaction, single-strand conformation polymorphism, and direct DNA sequencing in 105 subjects with primary hypertension and 70 subjects with diabetic nephropathy. One frequent polymorphism was identified, but its frequency did not differ among subjects with primary hypertension, subjects with diabetic nephropathy, or control subjects. Two of the 175 subjects with primary hypertension or diabetic nephropathy showed variants that were not present in 186 control subjects. None of the variants changed the PY-motif sequence. In conclusion, a betaArg564X mutation is the likely cause of Liddle's syndrome in this Swedish family, but it is unlikely that mutations in the beta- and gamma-subunit genes of the epithelial sodium channel play a significant role in the pathogenesis of primary hypertension or diabetic nephropathy.
Hypertension 1998 May
PMID:Mutations and variants of the epithelial sodium channel gene in Liddle's syndrome and primary hypertension. 957 23

The Sabra salt-sensitive SBH/y and salt-resistant SBN/y rats constitute a unique experimental model of hypertension in which salt-susceptibility is genetically determined and expressed only after salt-loading, without the development of spontaneous hypertension. To determine the genetic basis of salt-susceptibility in the Sabra rats, the candidate gene and total genome screen approaches were adopted. The likely candidate genes in this model incorporate salt-related physiological mechanisms such as the nitric oxide system, the arginine vasopressin axis and the epithelial sodium channel. In the random genome search scheme for culprit genes, SBH/y and SBN/y were cross-bred. A highly unusual and composite mode of transmission of salt-susceptibility was found in this cross, emphasizing the complexity of the genetic basis of salt-susceptibility. Linkage analysis of the entire rat genome with a large number of widely distributed microsatellite markers identified three putative gene loci on chromosomes 1 and 17 that contribute importantly to salt-sensitivity and/or resistance, and uncovered sex specificity in the role that salt-susceptibility genes fulfill in the development of hypertension.
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PMID:Genetic basis of salt-susceptibility in the Sabra rat model of hypertension. 960 81

Liddle's syndrome is an autosomal dominant form of salt sensitive hypertension caused by mutations in the beta or gamma subunit of the epithelial sodium channel. Systematic mutagenesis studies revealed that a conserved PPPXY sequence (PY motif) of the C-terminus of the alpha, beta, or gamma subunits might be involved in the regulation of the channel activity. However, only two missense mutations in the PY motif of the beta subunit have been reported to cause Liddle's syndrome. We sequenced the C-termini of the beta and gamma subunits of the epithelial sodium channel in a Japanese family clinically diagnosed as having Liddle's syndrome and found a new missense mutation in the PY motif of the beta subunit, P615S. Expression studies with P615S mutant in Xenopus oocytes resulted in an about 3-fold increase in the amiloride-sensitive sodium current compared to the wild type (p = 0.001). These findings provide further clinical evidence for the hypothesis that a conserved PY motif may be critically important for the regulation of the epithelial sodium channel.
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PMID:A family with Liddle's syndrome caused by a new missense mutation in the beta subunit of the epithelial sodium channel. 962 62

Hypertension is a common multifactorial disorder associated with considerable morbidity and mortality. The kidney plays a major role in the long term regulation of blood pressure. Liddle syndrome (pseudo-hyperaldosteronism) is one of a number of monogenic disorders of salt and water transport. In a kindred with at least four affected members suffering from Liddle syndrome, we confirmed by direct DNA sequencing the identity of a novel heterozygous mutation in h betaENaC, the gene encoding the beta subunit of the amiloride sensitive epithelial sodium channel which is expressed in the distal nephron. Single stranded conformational polymorphism analysis showed cosegregation of the mutant allele within the kindred with the Liddle phenotype. An insertion of an additional cytosine into a string of six located between codons 593 and 595 results in a sequence frameshift and is predicted to produce a protein truncated by 34 amino acids. The availability of a molecular diagnostic tool has implications for the management of hypertension and genetic counselling in families with Liddle syndrome.
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PMID:The diagnosis of Liddle syndrome by identification of a mutation in the beta subunit of the epithelial sodium channel. 964 96

In Liddle's syndrome, a rare inherited form of hypertension, epithelial sodium channel mutations appear to cause high blood pressure by increasing sodium reabsorption through sodium channels in the renal distal tubule. This increase in channel activity has not been confirmed previously by in vivo measurement. We have made transnasal potential difference measurements (effective in detection of increased sodium channel activity in cystic fibrosis) in three brothers with genetically proven Liddle's syndrome, their unaffected sister, and 40 normotensive controls. Maximum potential difference after 2 wk off treatment in the affected brothers was -30.4+/-1.2 mV (values mean+/-SD, lumen-negative with respect to submucosa) and was significantly more lumen-negative than that of the control group (-18.6+/-6.8 mV, P = 0.0228) or the unaffected sister (-18.25 mV, P < 0.01). The change in potential difference after topical application of 10(-)4 M amiloride was greater in the Liddle's patients, 14.0+/-2.1 mV, than in controls (7.9+/-3.9 mV, P = 0.0126) or the unaffected sister (5.5 mV, P < 0.05). This is the first in vivo demonstration of increased sodium channel activity in Liddle's syndrome. If these results are confirmed in other kindreds with this condition, then nasal potential difference measurements could provide a simple clinical test for Liddle's syndrome.
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PMID:Abnormalities of nasal potential difference measurement in Liddle's syndrome. 964 51

We describe a family with Liddle's disease caused by a novel mutation of the beta subunit of the human epithelial sodium channel (ENaC). A 15-year-old Japanese female was referred to our outclinic because of hypertension. The physical examination showed no abnormal findings except mild hypertension, but the laboratory data revealed low levels of plasma renin activity, plasma aldosterone and serum potassium. A comprehensive analysis of steroid hormones showed only high levels of urinary free cortisol and 17-hydroxycorticosteroids. During loading tests, blood pressure and serum potassium responded well to triamterene and slightly to spironolactone, but did not respond to dexamethasone. In addition, the normal ratio of tetrahydrocortisol plus 5alpha-tetrahydrocortisol to tetrahydrocortisone in a 24 h urinary excretion test strongly suggested a diagnosis of Liddle's disease rather than apparent mineralocorticoid excess syndrome. DNA sequence analysis of members of this family revealed a single cytosine base insertion at Arg-597 of the beta human ENaC in the proband and her mother, leading to a loss of the last 34 amino acids from the normally encoded protein as the result of a frameshift. We conclude that a de novo cytosine insertion into the final exon of the C-terminus of the beta human ENaC is responsible for Liddle's disease in this Japanese family.
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PMID:Identification of a single cytosine base insertion mutation at Arg-597 of the beta subunit of the human epithelial sodium channel in a family with Liddle's disease. 967 38

The kidney plays a dominant role in maintaining sodium homeostasis. Despite wide variation in environmental exposure, the osmolality of the extracellular fluid that is determined by the sodium ion concentration is maintained within narrow margins. Derangement in function of proteins that transport Na+ and of those regulating the activity of these sodium-transporting proteins are likely to be responsible for a number of clinical disorders of fluid and electrolyte homeostasis. The amiloride-sensitive epithelial sodium channel (ENaC) is implicated in the control of blood pressure as demonstrated by the analysis of two genetic diseases, Liddle's syndrome and pseudohypoaldosteronism (PHA-1). Mutations have been identified in the genes coding for the alpha-, beta- or gamma-subunit of ENaC. ENaC constitutes the limiting step for sodium reabsorption in epithelial cells that line the distal nephron, distal colon, ducts of several exocrine glands and lung airways and might play an important role in pathophysiological and clinical conditions such as hypertension or lung edema.
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PMID:Reversal of convention: from man to experimental animal in elucidating the function of the renal amiloride-sensitive sodium channel. 969 87

Hypertensives of African origin have low-renin, sodium-sensitive blood pressure and respond poorly to treatment with angiotensin converting enzyme inhibitors. The epithelial sodium channel may be important in the pathogenesis of essential hypertension in this population. This is supported by the identification of mutations within this channel, which lead to excess sodium reabsorption and hypertension in Liddle's syndrome. In this study we tested whether there was linkage of the genes encoding the three subunits of the epithelial sodium channel to essential hypertension in 63 affected sibling pairs of West African origin from St. Vincent and the Grenadines. We found no support for linkage of the epithelial sodium channel to essential hypertension in this population. However, further studies will be needed in larger populations of African ancestry to exclude a contribution of the genes encoding the epithelial sodium channel to hypertension.
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PMID:Absence of linkage of the epithelial sodium channel to hypertension in black Caribbeans. 971 86

For the past decade, hypertension research has shifted strongly in the direction of molecular genetics. The success stories are the monogenic hypertensive syndromes. Classic linkage analyses has located the responsible genes for glucocorticoid-remediable aldosteronism, Liddle syndrome, and apparent mineralocorticoid excess. The genes have been cloned and their function elucidated. Other monogenic syndromes are currently being intensively studied. However, in the area of primary hypertension, the successes have relied on the candidate gene approach. Allelic variants in the genes for angiotensinogen, alpha-adducin, beta2-adrenergic receptor, the G-protein beta3-subunit and the T594M mutation in the beta-subunit of the epithelial sodium channel have been identified; however, the importance of these allelic variants to primary hypertension as a whole, is not yet clear. A variant in the angiotensin-converting enzyme gene could not, initially, be convincingly associated with hypertension, but more recent analyses suggest an influence of the deletion allele on blood pressure in men, but apparently not in women. In all likelihood we are dealing with many genes with small effects. Affected sibling pair linkage analyses will probably not be successful in identifying the loci of these genes. To find new genes, novel approaches will be necessary, including searching for quantitative trait loci linked to blood pressure in normotensive persons, haplotype sharing methodology in trios and family units, the use of better study designs, and the investigation of isolated populations. Finally, rethinking the phenotype 'hypertension' and its intermediates must also receive priority.
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PMID:Molecular genetics of human hypertension. 988 71

In the general population blood pressure varies along a continuum and is regulated via multiple mechanisms involving many genetic loci and environmental factors. Epidemiological studies suggest that blood pressure variance is attributable to both genetic factors and environmental factors to the same magnitude. The molecular basis for three forms of sever hypertension transmitted on an autosomal basis has been recently elucidated: a) the glucocorticoid-suppressible aldosteronism (GSA), b) the Liddle's syndrome and c) the syndrome of apparent mineralocorticoid excess (AME). GSA is due to expression of a chimeric gene produced by fusion of the 11 beta-hydroxylase promoter with the region encoding the enzyme aldosterone-synthase. Expression of this chimeric gene occurs in the zona fasciculata of the adrenal cortex, under the control of ACTH, and can be suppressed by administration of glucocorticoids. Liddle's syndrome is due to mutations in the beta or gamma chain of the epithelial sodium channel in distal renal tubule cells. The hyperactivity of this channel caused by the mutations results in increased sodium reabsorption, which can be suppressed by administration of amiloride or triamterene. AME is caused by mutations of the 11 beta-hydroxysteroid dehydrogenase type 2 enzyme, an enzyme that metabolises cortisol into its receptor inactive keto-form cortisone, thus protecting the mineralocorticoid receptor from occupation by glucocorticoids. Apart from these rare genetic defects of the extended renin-angiotensin system, there are many susceptibility genes that might increase the risk of hypertension in a given environment. Several studies have demonstrated a link between the angiotensinogen gene and familial hypertension. One variant of angiotensinogen gene is associated with elevated plasma angiotensinogen levels and is more prevalent among hypertensive than among normotensive. This observation shows the relationship between the angiotensinogen genotype, the intermediate phenotype (i.e., plasma angiotensinogen elevation), and the distant phenotype (i.e., blood pressure elevation). The identification of these genes as well as other informative genetic markers distributed along the genome could be used in the search for genetic links between arterial hypertension and a chromosomal locus.
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PMID:[Molecular genetics of hypertension in the human]. 1006 28


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