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      Apoptosis of Tubular Epithelial Cells in Familial Juvenile Gouty Nephropathy

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          Two patients, a 47-year-old woman suffering from chronic renal failure, hyper- uricemia and gout, and her 26-year-old son with hyperuricemia and chronic renal failure, are described. The father and two siblings of the woman had died of chronic renal failure. Both patients had a markedly reduced fractional excretion of urate, which was significantly increased by both benzbromarone and probenecid. A renal biopsy of the son revealed an unspecific chronic tubulointerstitial nephropathy. By light microscopy, many proximal tubular epithelial cells showed signs of apoptosis, which was confirmed with the specific TUNEL assay. We propose a hypothesis based on a gain-of-function mutation of the luminal anion exchanger of the proximal tubulus to explain reduced uric acid excretion, dominant inheritance and apoptosis of tubular epithelial cells in this rare disease. Treatment with a combination of allopurinol to reduce the renal urate load and benzbromarone to block the tubular anion exchanger and normalize fractional uric acid excretion is suggested.

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          Most cited references 4

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          Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2.

          Inherited hypokalaemic alkalosis with low blood pressure can be divided into two groups-Gitelman's syndrome, featuring hypocalciuria, hypomagnesaemia and milder clinical manifestations, and Bartter's syndrome, featuring hypercalciuria and early presentation with severe volume depletion. Mutations in the renal Na-Cl cotransporter have been shown to cause Gitelman's syndrome. We demonstrate linkage of Bartter's syndrome to the renal Na-K-2Cl cotransporter gene NKCC2, and identify frameshift or non-conservative missense mutations for this gene that co-segregate with the disease. These findings demonstrate the molecular basis of Bartter's syndrome, provide the basis for molecular classification of patients with inherited hypokalaemic alkalosis, and suggest potential phenotypes in heterozygous carriers of NKCC2 mutations.
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            Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1.

            Autosomal recessive pseudohypoaldosteronism type I is a rare life-threatening disease characterized by severe neonatal salt wasting, hyperkalaemia, metabolic acidosis, and unresponsiveness to mineralocorticoid hormones. Investigation of affected offspring of consanguineous union reveals mutations in either the alpha or beta subunits of the amiloride-sensitive epithelial sodium channel in five kindreds. These mutations are homozygous in affected subjects, co-segregate with the disease, and introduce frameshift, premature termination or missense mutations that result in loss of channel activity. These findings demonstrate the molecular basis and explain the pathophysiology of this disease.
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              Liddle's syndrome: Heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel

              Liddle's syndrome (pseudoaldosteronism) is an autosomal dominant form of human hypertension characterized by a constellation of findings suggesting constitutive activation of the amiloride-sensitive distal renal epithelial sodium channel. We demonstrate complete linkage of the gene encoding the beta subunit of the epithelial sodium channel to Liddle's syndrome in Liddle's original kindred. Analysis of this gene reveals a premature stop codon that truncates the cytoplasmic carboxyl terminus of the encoded protein in affected subjects. Analysis of subjects with Liddle's syndrome from four additional kindreds demonstrates either premature termination or frameshift mutations in this same carboxy-terminal domain in all four. These findings demonstrate that Liddle's syndrome is caused by mutations in the beta subunit of the epithelial sodium channel and have implications for the regulation of this epithelial ion channel as well as blood pressure homeostasis.

                Author and article information

                S. Karger AG
                July 1998
                22 June 1998
                : 79
                : 3
                : 340-344
                a Department of Internal Medicine, Innsbruck University Hospital, and Institutes of b General and Experimental Pathology, and c Pathology, University of Innsbruck, Austria
                45060 Nephron 1998;79:340–344
                © 1998 S. Karger AG, Basel

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                Page count
                Pages: 5
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                Case Report

                Cardiovascular Medicine, Nephrology

                Gout, Hyperuricemia, Apoptosis


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