Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020438 (hypercalciuria)
 2,502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advances in the molecular genetics of inherited renal tubulopathies have allowed some insight into the normal mechanisms of tubular cation and anion reabsorption. It is now possible to view Bartter's syndrome, Gitelman's syndrome and pseudohypoaldosteronism type 1 as having genetic abnormalities which produce tubular defects that are similar to those induced by the pharmacological actions of loop diuretics, thiazide diuretics or potassium-sparing diuretics, respectively. Although these rare monogenic disorders with dramatic phenotypes seem to have little relevance to everyday clinical practice, it is possible that subtle abnormalities of the regulation of the ENaCs may play a role in low-renin forms of 'essential' hypertension. Similarly, subtle abnormalities in the function of the electroneutral sodium-(potassium)-chloride cotransporters (NKCC2 and NCCT) and the renal CLC-type chloride channels (CLC5) may be major determinants of urinary calcium excretion with roles in the pathogenesis of 'idiopathic' hypercalciuria and osteoporosis. Because of the intricate and diverse molecular mechanisms by which tubular reabsorption of water and solutes takes place in each different nephron segment, it is likely that other renal channels and transporters will be implicated in the pathogenesis of further monogenic disorders, and that these will allow additional insights into tubular functioning. Recent studies have demonstrated that in addition to abnormalities in the NKCC2 and ROMK1 genes, mutations at a third genetic locus can also cause Bartter's syndrome. Linkage studies, followed by mutational analyses have found deletions and point mutations in the gene encoding one of the TAL-specific chloride channels, CLCKB, in 17 Bartter's families. This chloride channel is similar in structure to CLC5, and is located on the long arm of chromosome 1. Importantly, there appears to be a phenotypic difference between subjects with Bartter's syndrome due to CLCKB abnormalities and those with NKCC2 or ROMK1 mutations. Despite the fact that all of these Bartter's patients had significant hypercalciuria, nephrocalcinosis was not found in any of the 17 subjects with CLCKB mutations, compared to 19 of 20 patients with NKCC2 or ROMK1 mutations. These findings have also demonstrated a key role for CLCKB as a major basolateral chloride channel involved in mTAL sodium and chloride reabsorption (Figure 2).
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PMID:Straightening out the renal tubule: advances in the molecular basis of the inherited tubulopathies. 951 7

Recent studies of hereditary renal tubular disorders have facilitated the identification and roles of chloride channels and cotransporters in the regulation of the most abundant anion, Cl-, in the ECF. Thus, mutations that result in a loss of function of the voltage-gated chloride channel, CLC-5, are associated with Dent's disease, which is characterized by low-molecular weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. Mutations of another voltage-gated chloride channel, CLC-Kb, are associated with a form of Bartter's syndrome, whereas other forms of Bartter's syndrome are caused by mutations in the bumetanide-sensitive sodium-potassium-chloride cotransporter (NKCC2) and the potassium channel, ROMK. Finally, mutations of the thiazide-sensitive sodium-chloride cotransporter (NCCT) are associated with Gitelman's syndrome. These studies have helped to elucidate some of the renal tubular mechanisms regulating mineral homeostasis and the role of chloride channels.
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PMID:Chloride channels in renal disease. 1056 51

Dent disease is an X-linked recessive disorder affecting the proximal tubule and is characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis/nephrolithiasis with a variable number of features of Fanconi syndrome. It is most often associated with mutations in CLCN5, which encodes the endosomal electrogenic chloride/proton exchanger ClC-5. Renal acidification abnormalities are only rarely seen in Dent disease, whereas the hypokalemic metabolic alkalosis associated with hyperreninemic hyperaldosteronism (Bartter-like syndrome) has been reported in only one patient so far. We report on a 5-year-old boy with Dent disease caused by mutation in CLCN5 gene, c.1073G>A, who presented with hypokalemic metabolic alkalosis and hyperreninemic hyperaldosteronism persisting over the entire follow-up. No mutations were found in NKCC2, ROMK, NCCT, or ClC-Kb genes. In addition, the patient exhibited growth failure associated with partial growth hormone (GH) deficiency. Coexistence of Bartter-like syndrome features with LMWP should prompt a clinician to search for Dent disease. The Bartter syndrome phenotype seen in Dent disease patients may represent a distinct form of Bartter syndrome, the exact mechanism of which has yet to be fully elucidated. Growth delay that persists in spite of appropriate therapy should raise suspicion of other causes, such as GH deficiency.
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PMID:A novel CLCN5 mutation in a boy with Bartter-like syndrome and partial growth hormone deficiency. 2068 Mar 51