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 is an autosomal recessive renal tubular disorder characterized by renal magnesium wasting, hypercalciuria, advanced nephrocalcinosis and progressive renal failure. Mutations in the paracellin-1 (CLDN16) gene have been defined as the underlying genetic defect. The tubular disorders and progression in renal failure are usually resistant to magnesium substitution and hydrochlorothiazide therapy, but hypomagnesemia may improve with advanced renal insufficiency. We present a patient with a homozygous truncating CLDN16 gene mutation (W237X) who had early onset of renal insufficiency despite early diagnosis at 2 months. He also had additional abnormalities including horseshoe kidney, neonatal teeth, atypical face, cardiac abnormalities including coarctation of the aorta associated with atrial and ventricular septal defects, umbilical hernia and hypertrichosis. To the best of our knowledge, this is the youngest case diagnosed as familial hypomagnesemia with hypercalciuria and nephrocalcinosis and the first case having such additional congenital abnormalities independent of the disease itself.
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PMID:Paracellin-1 gene mutation with multiple congenital abnormalities. 1692 49

Two knockout mouse models of Dent disease are similar with regard to the characteristics of Fanconi syndrome, but differ markedly with respect to vitamin D and renal calcium handling. One model exhibits hypercalciuria, renal calcifications and renal failure; the other does not. Data from such experimental models have greatly advanced our understanding of the molecular mechanisms underlying Dent disease. This Review summarizes some of the important phenotypic characteristics shared by mouse models and people with Dent disease. Experimental data are used to predict the molecular mechanisms underlying this disease. Receptor-mediated endocytosis and the mistargeting of megalin, cubilin, the sodium/proton exchanger Nhe3 and the sodium/phosphate transporter Napi-2a will be reviewed, and the causes of mistargeting will be discussed. Kidney stones and renal failure are prominent features of Dent disease. Investigations using a mouse model with nephrocalcinosis and renal failure indicate that citrate therapy delays the onset of these processes in Dent disease. Throughout this Review, questions that might underpin new areas of investigation are proposed.
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PMID:Mechanisms of disease: what can mouse models tell us about the molecular processes underlying Dent disease? 1765 24

Bartter syndrome (BS) type 1, also referred to antenatal BS, is a genetic tubulopathy with hypokalemic metabolic alkalosis and prenatal onset of polyuria leading to polyhydramnios. It has been shown that BS type 1 is caused by mutations in the SLC12A1 gene encoding bumetanide-sensitive Na-K-2Cl (-) cotransporter (NKCC2). We had the opportunity to care for two unrelated Japanese patients of BS type 1 with typical manifestations including polyhydramnios, prematurity, hypokalemia, alkalosis, and infantile-onset nephrocalcinosis. Analysis of the SLC12A1 gene demonstrated four novel mutations: N117X, G257S, D792fs and N984fs. N117X mutation is expected to abolish most of the NKCC2 protein, whereas G257, which is evolutionary conserved, resides in the third transmembrane domain. The latter two frameshift mutations reside in the intra-cytoplasmic C-terminal domain, which illustrates the importance of this domain for the NKCC2 function. In conclusion, we found four novel SLC12A1 mutations in two BS type 1 patients. Development of effective therapy for hypercalciuria is mandatory to prevent nephrocalcinosis and resultant renal failure.
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PMID:Novel SLC12A1 (NKCC2) mutations in two families with Bartter syndrome type 1. 1799 60

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

Congenital chloride diarrhea is due to mutations in the intestinal Cl(-)/HCO(3)(-) exchange (SLC26A3) which results in sodium chloride and fluid depletion leading to hypochloremic and hypokalemic metabolic alkalosis. Although treatment with sodium and potassium chloride offers protection from renal involvement in childhood, the long-term renal outcome remains unclear. Here we describe two cases of congenital chloride diarrhea-associated end-stage renal disease with transplantation. Further, we show that there is a high incidence of mild chronic kidney disease in 35 other patients with congenital chloride diarrhea. The main feature of the renal injury was nephrocalcinosis, without hypercalciuria or nephrolithiasis with small sized kidneys and commensurately reduced glomerular filtration rates. This suggests that diarrhea-related sodium chloride and volume depletion, the first signs of non-optimal salt substitution, promote urine supersaturation and crystal precipitation. The poor compliance with salt substitution along with long-lasting hypochloremic and hypokalemic metabolic alkalosis is likely to induce progressive calcification and renal failure. Both our patients developed nephrocalcinosis in the transplanted kidneys suggesting that this complication is a consequence of intestinal SLC26A3 deficiency. Interestingly, the transporter is expressed in the distal nephron but the recurrence of nephrocalcinosis in the transplanted kidney suggests that it does not play a significant renal role in this syndrome.
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PMID:The impact of sodium chloride and volume depletion in the chronic kidney disease of congenital chloride diarrhea. 1882

In humans, Dent's disease, an X-linked renal tubular disorder, is characterized by low molecular weight proteinuria, aminoaciduria, glycosuria, hyperphosphaturia, hypercalciuria, nephrolithiasis, progressive renal failure and sometimes rickets or osteomalacia. The aetiology of X-linked Dent's disease is established to be caused by mutations of the CLCN5 gene. The protein product of this gene is the voltage-gated chloride-proton exchanger CLC-5. Previous studies by the Johns Hopkins group (Guggino) and the Hamburg group (Jentsch) have established that the Clcn5 knockout mouse recapitulates the renal attributes of Dent's disease. In order to understand the changes in kidney function that accompany the knockout of the Clcn5 gene, we examined gene expression profiles from dissected proximal segment 1 (S1) and segment 2 (S2) tubules of mouse kidneys. Overall, 725 genes are expressed differentially in the proximal tubules of the Dent Clcn5 knockout mouse model compared with those of control wild-type mice. A major finding is the change in the cholesterol synthesis pathway. Some interesting changes also occur in genes encoding transport proteins. One of these transport proteins, the sodium bile cotransporter gene, Slc10a2, has transcripts increased by 17-fold in the Clcn5 knockout mouse. The Clc-3 protein encoded by Clcn3, a chloride-proton exchanger related to Clc-5, has a 1.9-fold increase in transcripts. The Npt2c protein, a proximal tubule sodium phosphate cotransporter encoded by Slc34a3, has a 0.6-fold decrease in the number of transcripts. The sodium-proton exchanger-like protein, Nhe10/sperm, encoded by Slc9a10, has a 0.5-fold decrease in transcript number. These genes are discussed with regard to the possible physiological outcomes of their transcript or protein changes.
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PMID:Can we generate new hypotheses about Dent's disease from gene analysis of a mouse model? 1893 Oct 44

Absorptive hypercalciuria (AH) is associated with elevated levels of 1,25-dihydroxyvitamin D (1,25(OH)(2)D). While no increase of 1,25(OH)(2)D after oral administration of 25-hydroxyvitamin D (25OHD) at high doses has been claimed in normal subjects, a substrate-product relationship has been reported in normal children, young people after UV irradiation, older persons, postmenopausal women, primary hyperparathyroidism, renal failure, osteomalacia, and sarcoidosis. No data of this relationship in AH is available. To investigate 25OHD-1,25(OH)(2)D substrate-product relationship in AH, 161 AH patients (mean age 60.9+/-11.7 years) and 110 age- and sex-matched controls (mean age 61.5+/-12.4 years) were studied. In 57 controls and 52 AH subjects 25OHD-1,25(OH)(2)D relationship in basal conditions and after 2-week oral 25OHD (25 microg/day) administration were evaluated. In basal conditions 25OHD and 1,25(OH)(2)D were correlated in both, controls and AH; 25OHD treatment was followed by an increase in serum 25OHD and 1,25(OH)(2)D in both groups. However, delta responses of 25OHD and 1,25(OH)(2)D to 25OHD were higher in AH suggesting an enhanced activity of 1 alpha-hydroxylase. In conclusion, the higher response of 1,25(OH)(2)D after oral 25OHD in AH patients suggests a differential capacity between both groups in handling the increases in 1,25(OH)(2)D.
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PMID:Vitamin D substrate-product relationship in idiopathic hypercalciuria. 1901 26

Dent's disease is an X-linked hereditary renal tubular disorder characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets and progressive renal failure. About 60% of patients have mutations in the CLCN5 gene (Dent 1), which encodes a kidney-specific chloride/proton antiporter, and 15% of patients have mutations in the OCRL1 gene (Dent 2). The aim of the study was to identify CLCN5 mutations in Jewish Israeli families with Dent's disease and to characterize the associated clinical syndromes. We studied 17 patients from 14 unrelated Israeli families with a clinical diagnosis of Dent's disease. LMWP was detected in all patients. Most of the affected individuals had hypercalciuria and nephrocalcinosis. Renal stones were found in 1 patient, and renal insufficiency developed in 2 patients. We identified six different truncating CLCN5 mutations that were segregated with the disease in 7 families: three nonsense mutations (Arg28stop, Arg467stop and Arg637stop), one deletion mutation (505delA) and two novel mutations, consisted of one deletion mutation (1493delG) and one insertion mutation (409insC). All the mutations cause premature termination of protein translation and result in a non-functional truncated protein. The clinical characteristics of patients with different mutations were, in general, similar.
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PMID:Truncating mutations in the chloride/proton ClC-5 antiporter gene in Seven Jewish Israeli families with Dent's 1 disease. 1954 86

Renal tubular reabsorption is important for extracellular fluid homeostasis and much of this occurs via the receptor-mediated endocytic pathway. This pathway is disrupted in Dent's disease, an X-linked renal tubular disorder that is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. Dent's disease is due to mutations of CLC-5, a chloride/proton antiporter, expressed in endosomes and apical membranes of renal tubules. Loss of CLC-5 function alters receptor-mediated endocytosis and trafficking of megalin and cubilin, although the underlying mechanisms remain to be elucidated. Here, we report that CLC-5 interacts with kinesin family member 3B (KIF3B), a heterotrimeric motor protein that facilitates fast anterograde translocation of membranous organelles. Using yeast two-hybrid, glutathione-S-transferase pull-down and coimmunoprecipitation assays, the COOH terminus of CLC-5 and the coiled-coil and globular domains of KIF3B were shown to interact. This was confirmed in vivo by endogenous coimmunoprecipitation of CLC-5 and KIF3B and codistribution with endosomal markers in mouse kidney fractions. Confocal live cell imaging in kidney cells further demonstrated association of CLC-5 and KIF3B, and transport of CLC-5-containing vesicles along KIF3B microtubules. KIF3B overexpression and underexpression, using siRNA, had reciprocal effects on whole cell chloride current amplitudes, CLC-5 cell surface expression, and endocytosis of albumin and transferrin. Clcn5(Y/-) mouse kidneys and isolated proximal tubular polarized cells showed increased KIF3B expression, whose effects on albumin endocytosis were dependent on CLC-5 expression. Thus, the CLC-5 and KIF3B interaction is important for CLC-5 plasma membrane expression and for facilitating endocytosis and microtubular transport in the kidney.
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PMID:CLC-5 and KIF3B interact to facilitate CLC-5 plasma membrane expression, endocytosis, and microtubular transport: relevance to pathophysiology of Dent's disease. 1994 36

Pediatric urolithiasis is an endemic disease in Turkey. We evaluated the clinical, radiological and metabolic features of children with urolithiasis in Western Turkey. We retrospectively reviewed the records of 85 children with urolithiasis who were followed-up between 2004 and 2010 in Pediatric Nephrology Department of Celal Bayar University, Manisa. The male/female ratio was 1.23/1. The mean age at diagnosis was 66.1 months (range 3-210 months). Family history of urolithiasis was found in 58 (68.2%) patients. 23 (27%) patients were born from consanguineous marriages. Stones were located in the upper urinary tract in 79 (92.9%) patients. In 66 (77.6%) patients, stones were single-sided and 41 (48.2%) patients had multiple stones. Calcium oxalate stones were the most common one among patients in whom stone analysis was performed (78.5%). Hypocitraturia was the most commonly detected urinary metabolic risk factor. In patients who were under 12 months of age at diagnosis, hypercalciuria was the most commonly seen urinary metabolic risk factor. At the end of follow-up period, 24 patients became free of stone disease and 4 patients had recurrence. In conclusion, metabolic abnormalities are common in pediatric stone patients and are strongly associated with recurrence. Considering that urolithiasis in children is an important risk factor for renal failure, early diagnosis, detailed metabolic evaluation and implementing appropriate treatment and follow-up protocols may prevent recurrence and renal damage.
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PMID:Metabolic and demographic characteristics of children with urolithiasis in Western Turkey. 2065 90


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