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)

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder characterized by excessive renal magnesium and calcium wasting, eventually, progressing to renal failure. It has been recently attributed to a mutation in the Claudin 16 (CLDN 16) gene of the Paracellin-1 (PCLN-1) tight junction protein. Herein, we report 2 sisters with FHHNC. Both sisters presented at an early stage with hypomagnesemia and hypocalcemia. The first patient was initially mislabeled and treated as a case of hypoparathyroidism, while the second patient was diagnosed retrospectively after the diagnosis of her sister. The 2 patients developed end stage renal disease.
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PMID:Familial hypomagnesemia with hypercalciuria and nephrocalcinosis in 2 sisters. 1832 78

Renal stone disease (nephrolithiasis) affects 3-5% of the population and is often associated with hypercalciuria. Hypercalciuric nephrolithiasis is a familial disorder in over 35% of patients and may occur as a monogenic disorder that is more likely to manifest itself in childhood. Studies of these monogenic forms of hypercalciuric nephrolithiasis in humans, e.g. Bartter syndrome, Dent's disease, autosomal dominant hypocalcemic hypercalciuria (ADHH), hypercalciuric nephrolithiasis with hypophosphatemia, and familial hypomagnesemia with hypercalciuria have helped to identify a number of transporters, channels and receptors that are involved in regulating the renal tubular reabsorption of calcium. Thus, Bartter syndrome, an autosomal disease, is caused by mutations of the bumetanide-sensitive Na-K-Cl (NKCC2) co-transporter, the renal outer-medullary potassium (ROMK) channel, the voltage-gated chloride channel, CLC-Kb, the CLC-Kb beta subunit, barttin, or the calcium-sensing receptor (CaSR). Dent's disease, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrolithiasis, is due to mutations of the chloride/proton antiporter 5, CLC-5; ADHH is associated with activating mutations of the CaSR, which is a G-protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium-phosphate co-transporter (NPT2c); and familial hypomagnesemia with hypercalciuria is due to mutations of paracellin-1, which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier in a variety of epithelia. These studies have provided valuable insights into the renal tubular pathways that regulate calcium reabsorption and predispose to hypercalciuria and nephrolithiasis.
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PMID:Genetic causes of hypercalciuric nephrolithiasis. 1844 82

The past decade has witnessed multiple advances in our understanding of magnesium (Mg(2+)) homeostasis. The discovery that mutations in claudin-16/paracellin-1 or claudin-19 are responsible for familial hypomagnesemia with hypercalciuria and nephrocalcinosis provided insight into the molecular mechanisms governing paracellular transport of Mg(2+). Our understanding of the transcellular movement of Mg(2+) was similarly enhanced by the realization that defects in transient receptor potential melastatin 6 (TRPM6) cause hypomagnesemia with secondary hypocalcemia. This channel regulates the apical entry of Mg(2+) into epithelia. In so doing, TRPM6 alters whole-body Mg(2+) homeostasis by controlling urinary excretion. Consequently, investigation into the regulation of TRPM6 has increased. Acid-base status, 17beta estradiol, and the immunosuppressive agents FK506 and cyclosporine affect plasma Mg(2+) levels by altering TRPM6 expression. A mutation in epithelial growth factor is responsible for isolated autosomal recessive hypomagnesemia, and epithelial growth factor activates TRPM6. A defect in the gamma-subunit of the Na,K-ATPase causes isolated dominant hypomagnesemia by altering TRPM6 activity through a decrease in the driving force for apical Mg(2+) influx. We anticipate that the next decade will provide further detail into the control of the gatekeeper TRPM6 and, therefore, overall whole-body Mg(2+) balance.
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PMID:Molecular determinants of magnesium homeostasis: insights from human disease. 1856 69

Claudin-16 is defective in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Claudin-16 knockdown (CLDN16 KD) mice show reduced cation selectivity in the thick ascending limb. The defect leads to a collapse of the lumen-positive diffusion voltage, which drives Ca(2+) and Mg(2+) absorption. Because of the reduced tight junction permeability ratio for Na(+) over Cl(-), we proposed a backleak of NaCl into the lumen. Systemic analysis had revealed lower blood pressure and a moderately increased plasma aldosterone concentration. In this study, we measured the amiloride-sensitive equivalent short-circuit current in isolated, perfused collecting ducts and found it increased by fivefold in CLDN16 KD mice compared with wild-type (WT) mice. Amiloride treatment unmasked renal Na(+) loss in the thick ascending limb of the nephron. Under amiloride treatment, CLDN16 KD mice developed hyponatremia and the renal fractional excretion of Na(+) was twofold higher in CLDN16 KD compared with WT mice. The loss of claudin-16 also resulted in increased urinary flow, reduced HCO(3)(-) excretion, and lower urine pH. We conclude that perturbation in salt and acid-base metabolism in CLDN16 KD mice has its origin in the defective cation permselectivity of the thick ascending limb of the nephron. This study has contributed to the still incomplete understanding of the symptoms of FHHNC patients.
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PMID:Salt and acid-base metabolism in claudin-16 knockdown mice: impact for the pathophysiology of FHHNC patients. 1878 60

Claudin-16 (paracellin-1) is a tight junction protein localized mainly in the thick ascending limb of Henle's loop and also in the distal nephron. Its defect causes familial hypomagnesaemia with hypercalciuria and nephrocalcinosis. This had been taken as an indication that claudin-16 conveys paracellular Mg(2+) and Ca(2+) transport; however, evidence is still conflicting. We studied paracellular ion permeabilities as well as effects of claudin-16 on the driving forces for passive ion movement. MDCK-C7 cells were stably transfected with wild-type (wt) and mutant (R146T, T233R) claudin-16. Results indicated that paracellular permeability to Mg(2+) but not to Ca(2+) is increased in cells transfected with wt compared to mutant claudin-16 and control cells. Increased basolateral Mg(2+) concentration activated a transcellular Cl(-) current which was greatly enhanced in cells transfected with wt and T233R claudin-16, as compared to R146T claudin-16-transfected or control cells. This current was triggered by the basolateral calcium-sensing receptor causing Ca(2+) release from internal stores, thus activating apical Ca(2+)-sensitive Cl(-) channels and basolateral Ca(2+)-sensitive K(+) channels. Immunohistochemical data suggest that the Cl(-) channel involved is bestrophin. We conclude that claudin-16 itself possesses only moderate paracellular Mg(2+) permeability but governs transcellular Cl(-) currents by interaction with apical Ca(2+)-activated Cl(-) channels, presumably bestrophin. As the transepithelial voltage generated by such a current alters the driving force for all ions, this may be the major mechanism to regulate Mg(2+) and Ca(2+) absorption in the kidney.
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PMID:Claudin-16 affects transcellular Cl- secretion in MDCK cells. 1952 48

Claudin-16 (CLDN16) is critical for renal paracellular epithelial transport of Ca(2+) and Mg(2+) in the thick ascending loop of Henle. To gain novel insights into the role of CLDN16 in renal Ca(2+) and Mg(2+) homeostasis and the pathological mechanisms underlying a human disease associated with CLDN16 dysfunction [familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), OMIM 248250], we generated a mouse model of CLDN16 deficiency. Similar to patients, CLDN16-deficient mice displayed hypercalciuria and hypomagnesemia. Contrary to FHHNC patients, nephrocalcinosis was absent in our model, indicating the existence of compensatory pathways in ion handling in this model. In line with the renal loss of Ca(2+), compensatory mechanisms like parathyroid hormone and 1,25(OH)(2)D(3) were significantly elevated. Also, gene expression profiling revealed transcriptional upregulation of several Ca(2+) and Mg(2+) transport systems including Trpv5, Trpm6, and calbindin-D9k. Induced gene expression was also seen for the transcripts of two putative Mg(2+) transport proteins, Cnnm2 and Atp13a4. Moreover, urinary pH was significantly lower when compared with wild-type mice. Taken together, our findings demonstrate that loss of CLDN16 activity leads to specific alterations in Ca(2+) and Mg(2+) homeostasis and that CLDN16-deficient mice represent a useful model to further elucidate pathways involved in renal Ca(2+) and Mg(2+) handling.
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PMID:Targeted deletion of murine Cldn16 identifies extra- and intrarenal compensatory mechanisms of Ca2+ and Mg2+ wasting. 2014 68

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive renal tubular disorder that typically presents with disturbances in magnesium and calcium homeostasis, recurrent urinary tract infections, and polyuria and/or polydipsia. Patients with FHHNC have high risk of the development of chronic kidney disease and end-stage renal disease in early adolescence. Multiple distinct mutations in the CLDN16 gene, which encodes a tight junction protein, have been found responsible for this disorder. In addition, mutations in another member of the claudin family, CLDN19, were identified in a subset of patients with FHHNC with visual impairment. The claudins belong to the family of tight junction proteins that define the intercellular space between adjacent endo- and epithelial cells. Claudins are especially important for the regulation of paracellular ion permeability. We describe a Brazilian family with 2 affected siblings presenting with the typical FHHNC phenotype with ocular anomalies. The clinical diagnosis of FHHNC was confirmed using mutational analysis of the CLDN19 gene, which showed 2 compound heterozygous mutations. In the context of the case vignette, we summarize the clinical presentation, diagnostic criteria, and therapeutic options for patients with FHHNC. We also review recent advances in understanding the electrophysiologic function of claudin-16 and -19 in the thick ascending limb of the loop of Henle and implications for ion homeostasis in the human body.
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PMID:The role of tight junctions in paracellular ion transport in the renal tubule: lessons learned from a rare inherited tubular disorder. 2118 73

The integral tight junction protein Claudin-16 (Cldn16) is predominantly expressed in renal epithelial cells of the thick ascending limb of Henle's loop where, together with claudin-19, it forms a cation-selective pore that allows influx of Na+ from the interstitial fluid into the lumen of the kidney tubule. This leads to an electrochemical gradient that drives the reabsorbtion of Mg2+ and Ca2+ ions from the renal filtrate. Mutations in the Cldn16 gene have been identified in patients suffering from familial hypomagnesemia with hypercalciuria and nephrocalcinosis, with excessive renal wastage of Mg2+ and Ca2+ being a hallmark of this condition. Studies into the mechanism by which mutations impair Cldn16 function have shown that although several mutations affect paracellular ion transport, many interfere with intracellular trafficking of Cldn16, ultimately compromising its localization to TJs. Here, we describe the experimental approaches that can be used to monitor intracellular localization and trafficking of Cldn16. These methods can easily be adapted to study other claudins, provided suitable antibodies are available.
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PMID:Methods to analyze subcellular localization and intracellular trafficking of Claudin-16. 2171 54

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is caused by a mutation in the gene CLDN16, which encodes paracellin 1 (claudin-16), atight junction protein mediating paracellular transport which is expressed in the thick ascending loop of Henle and in the distal convoluted tubule, where reabsorption of magnesium occurs. We present a 4 years old Turkish female child with a chief complaint of hypocalcemic tetany. A diagnosis of FHHNC was confirmed by genetic testing for a mutation in claudin 16 gene. Claudin 16 gene revealed homozygosity for the p.K183E(AAA>GAA) C. 547A>G indicating the diagnosis of hypomagnesemia with hypercalciuria and nephrocalcinosis. To our knowledge, this is the first case of FHHNC reported in Turkish population diagnosed at molecular level.
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PMID:A novel mutation of the claudin 16 gene in familial hypomagnesemia with hypercalciuria and nephrocalcinosis mimicking rickets. 2184 11

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive tubular disorder characterized by excessive renal magnesium and calcium excretion and chronic kidney failure. This rare disease is caused by mutations in the CLDN16 and CLDN19 genes. These genes encode the tight junction proteins claudin-16 and claudin-19, respectively, which regulate the paracellular ion reabsorption in the kidney. Patients with mutations in the CLDN19 gene also present severe visual impairment. Our goals in this study were to examine the clinical characteristics of a large cohort of Spanish patients with this disorder and to identify the disease causing mutations. We included a total of 31 patients belonging to 27 unrelated families and studied renal and ocular manifestations. We then analyzed by direct DNA sequencing the coding regions of CLDN16 and CLDN19 genes in these patients. Bioinformatic tools were used to predict the consequences of mutations. Clinical evaluation showed ocular defects in 87% of patients, including mainly myopia, nystagmus and macular colobomata. Twenty two percent of patients underwent renal transplantation and impaired renal function was observed in another 61% of patients. Results of the genetic analysis revealed CLDN19 mutations in all patients confirming the clinical diagnosis. The majority of patients exhibited the previously described p.G20D mutation. Haplotype analysis using three microsatellite markers showed a founder effect for this recurrent mutation in our cohort. We also identified four new pathogenic mutations in CLDN19, p.G122R, p.I41T, p.G75C and p.G75S. A strategy based on microsequencing was designed to facilitate the genetic diagnosis of this disease. Our data indicate that patients with CLDN19 mutations have a high risk of progression to chronic renal disease.
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PMID:Claudin-19 mutations and clinical phenotype in Spanish patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. 2330 Oct 36


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