Archive for the ‘Disease’ Category

distal renal tubular acidosis (dRTA)

It is known that subtle forms of dRTA can occur only with hy- percalciuria and recurrent calcium nephrolithiasis. Thus, it is possible that the same molecular defects responsible for the full range dRTA are also causative of cases of familial and spo­radic forms of PH and ICN. As yet, both the ss1 subunit of the vacuolar H+-ATPase (ATP6B1) and the carbonic anhydrase II genes have not been investigated in sporadic and familial forms of ICN. On the contrary the possible existence of a link­age between the Anione Exchanger (A E1) locus and familial ICN was the working hypothesis of a previous study of Gam- baro et al. They formerly described the association of an anom­alous erythrocyte oxalate self-exchange with ICN, dependent on an abnormal phosphorylation of the AE1-band 3 exchanger. Physiological and clinical studies showed the rele­vance of this defect on ICN, and interestingly subclinical acidifi­cation defects were disclosed in stone patients with the ery­throcyte anomaly. In a family study, the abnormal erythro- cyte oxalate self-exchange appeared to be genetically deter­mined, segregating as a Mendelian autosomal dominant trait, although polygenic inheritance could not be excluded. However, a linkage analysis between the 17q21-qter loci, con­taining the AE1 gene and the abnormal oxalate self-exchange, in 2 of three-generation families with renal stones was negative. Thus, the suggested hypothesis is that the erythrocyte ox- alate self-exchange is an intermediate phenotype, possibly with a polygenic determination. Canadian Drugstore 


As discussed, the frequencies of dominant and recessive re­nal-stone-related conditions are uncommon to rare, reflecting the rarity of mutated genes producing them. In these disorders the inheritance of one or a couple of defective alleles is neces­sary and sufficient to induce the disease in the absence of any particular environmental factors. In polygenic diseases the indi­vidual genes by per se are not capable to cause the disease; but individual environmental factors are also incapable to de­termine the disease. However, individual genes and environ­mental factors, in various combinations, account for common types of calcium nephrolithiasis. We have already discussed that mutations of genes involved in monogenic disorders were not found in sporadic idiopathic stone formers. However, a pos­sible explanation is that some of candidate, and still unknown genes, have to be analyzed in this regard; alternatively, only a small subset of PH and ICN patients has a Mendelian disorder. Similar considerations suggest the possibility that mutations in the AE1 gene or in the ATP6B1 gene which have been de­scribed in recessive forms of dRTA are responsible for spo­radic PH and ICN. Subtle defects in renal acidification, and hypocitraturia, in some cases markers of mild form of dRTA, are too much frequently observed in idiopathic patients. On the contrary, familial dRTA, particularly the recessive forms, are extremely rare conditions.


Disorders of renal phosphate wasting may lead to hypophos- phatemia, increase of 1,25(OH)2D3 and consequent excess of intestinal calcium absorption and hypercalciuria. A clear exam­ple is represented by Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH), a phenotype similar, except for bone, to that of mice with deletion of the kidney-specific sodium-phosphate co-transporter gene, N p t 2. Mutational analysis of human Npt2a gene has been performed by Prie et al identifying two patients (2 out of 20) carrying NPT2a mutations, exhibiting urolithiasis or osteoporosis and persistent idiopathic hypophosphatemia, associated with a decrease in maximal renal phosphate reabsorption. Npt2a gene localizes at chromosome 5q35. One of the 2 subjects was a man with re­current renal stones, hypophosphatemia, and reduced renal phosphate reabsorption; the second patient was a 64-year-old woman with idiopathic bone demineralization, hypophos- phatemia, and reduced renal phosphate reabsorption. Her only daughter, who also had the mutation, had a spinal deformity and a history of arm fractures, with hypophosphatemia and low maximal renal phosphate reabsorption. NPT2a is a renal proxi­mal tubular, brush-border membrane Na+-phosphate co-trans­porter. Both NPT2a gene mutations (V147M and A48F) had a dominant negative effect on the phosphate-induced current in oocytes co-transfected with the wild and mutant RNAs. This may explain why these mutations may lead to an impairment in renal phosphate reabsorption, resulting in hypophosphatemia.  Discount drugs online

A low serum phosphate concentration, in turn, would be ex­pected to increase 1,25-(OH)2D3 production, leading to increased intestinal absorption of calcium and hypercalciuria. As mentioned above, this phenotype resembles that of heterozygous N p t 2 a deficient mice, with increased urinary phosphate and calcium excretion, elevated plasma concentra­tions of 1,25-(OH)2D3 (51), and nephrocalcinosis. These findings were consistent with a dominant negative effect of the mutant proteins on the function of the wild type carrier, leading to a substantial renal phosphate losses in heterozygous pa­tients. However, as correctly pointed out by Scheinman and Tenenhouse, this is at odds with the model with the target­ed inactivation of Npt2 gene, where the heterozygous animals have neither hypercalciuria nor nephrocalcinosis. The rea­son why renal phosphate leak leads to either calcium stones or bone demineralization is still unknown, although it might be due to gender, environmental factors, or other genetic differences. Although they did not search for mutations in introns or regula­tory regions of the NPT2a gene, other genes may also be in­volved in the renal phosphate leak in patients who did not dis­close NPT2a gene mutations. The reported mother to daughter mutation segregation suggests an autosomal dominant inheri­tance, but up to date no systematic analysis of kindreds with similar clinical phenotype has been performed.


Familial Hypomagnesaemia with Hypercalciuria and Nephro­calcinosis (FHHN) is a rare disorder of calcium and magnesium paracellular transportation at TAL level depending on muta­tions of P L C N – 1 gene. The gene product, paracellin-1 or claudin, is essential in the regulation of the paracellular path­way permeability at TAL level and its alteration determines a decrease of calcium and magnesium reabsorption. A striking incidence of hypercalciuria, and nephrolithiasis among family members not affected by FHHNC was observed by We­ber et al in 13 of 23 families and 11 cases (42%) out of 26 members of 4 affected families. In this study most of the non-FHHNC subjects presenting with hypercalciuria and/or nephrolithiasis were obligate carriers of heterozygous PCLN-1 mutations. It seems therefore reasonable to propose a relation­ship between sporadic hypercalciuria or stone disease and mu­tations in the PCLN-1 gene. It might be expected that mutation analysis of kindreds affected by familial hypercalciuria with nephrocalcinosis and/or nephrolithiasis (with an apparently dominant mode of inheritance) would demonstrate heterozy­gous mutations in the PCLN-1 gene in some of them. Unfortu­nately, this kind of study has yet to be performed.  cheap canadian drugs

CaSR gene-dependent hypercalciuric diseases

C a S R gene activating mutations of the extracellular domain, resulting in a gain of function, have been originally described to be associated with hypocalcaemia in kindreds. Carling et al. recently described a kindred with 20 affected individ­uals in whom the hypercalcemic trait segregated, in an autosomal dominant manner, with inappropriately higher serum PTH and magnesium levels and urinary calcium levels than in unaf­fected members. Presumably, the hypercalciuria in this family may be secondary to the presence of hypercalcaemia due to primary hyperparathyroidism.


Genetics of primary hypercalciuria: NKCC2, ROMK, and CLCNKB genes

Jul 27, 2011 Author: Walter Mcneil | Filed under: Disease

NKCC2, ROMK, and CLCNKB genes

Mutations of these genes account for the highly genetic hetero­geneous disorder represented by Bartter’s syndrome. This dis­ease consists of a set of renal tubular disorders, inherited as autosomal recessive trait, clinically characterized by chronic hypokaliemia, metabolic alkalosis, hyperreninism and hyperal- dosteronism with normal values of blood pressure: Antenatal (with hyperproduction of type E Prostaglandins) and Classical forms of Bartter’s syndrome. PH is presented on both these forms. Other additional biochemical and clinical features deter­mine a different tubulopathies phenotype classification: Antenatal form consists of type I, II and IV Bartter’s syndrome, while Classical form is also indicated as type III Bartter’s syn­drome. Mutations of the responsible genes create a se­vere disturbance in maintaining the electric driving force at tubular level regulating the paracellular transportation (from lu­men to blood) of calcium. 1 internet online drugstore

NKCC2 gene. It encodes for the Na+/K+/Cl2 co-transporter, a membrane protein expressed on the lumen side of tubular cells at TAL level, that physiologically determines the entry of the above-described ions from lumen within the cell. Its mutations have been reported in Antenatal Bartter’s syndrome preventing the entry of Na+/K+/Cl2 from the lumen side.


After identification of chromosomal localization of disease-gene by linkage approach in kindreds affected by hypercalciuria and/or calcium nephrolithiasis, many Authors also identified the disease-causing gene itself, whose mutations have also been evaluated in sporadic cases of PH. Hence, disease-causing mutations and functional variants, namely polymorphisms, of the same genes have been analyzed in order to detect the PH susceptibility genotype. Due to no homogeneity of patients suf­fering for PH and Idiopathic Nephrocalcinosis (ICN), subsets of sporadic cases might be due to mutations or polymorphic vari­ants in different candidate genes. However, up to now avail­able results do not support the hypothesis that the described gene mutations and polymorphisms have a significant role in the majority of sporadic PH and ICN cases. Cheap generic drugs online 

CLCN5 gene

CLCN5 gene encodes for a chloride channel protein, expressed in several human cells and in particular localized to the S3 seg­ment of the proximal tubule and to medullary thick ascending limb (mTAL). Subsequent subcellular fractionation studies indi­cate that CLCN5 is localized to endosomes and it is impor­tant for tubular reabsorption of low molecular weight proteins. Several Mendelian CLCN5 gene mutations-depending pheno­types have been described: X linked hypercalciuria nephrolithia­sis, Dent’s disease, X linked recessive rickets, low molecular weight proteinuria/nephrocalcinosis, Idiopathic nephrolithiasis, all including PH. Frymoyer et al. described a man with an inactivating mutation in the CLCN5 gene who did not have low molecular weight proteinuria (together with the other features of the Dent’s disease) and whose unique biochemical abnormality was hypercalciuria.


Familial studies display that calcium excretion is correlated be­tween sib-pairs, brothers and sisters, parents and children, but not between spouses (Figure 2) that do not share a common genetic background. Thus, a great portion of calcium excretion variability appears to be explained by hereditary factors. The proportion of calcium excretion variance is indicated by the cor­relation coefficient in offspring-parents. In the considered families, approximately 50% of the calcium excretion variance is justified by additive effect of genes (r=0.474, n=63, p=0.0001, Figure 2). In human pedigrees, hypercalciuria can be detected at each generation, with a sex independent trans­mission and no concordance for hypercalciuria in wives and husbands. These familial studies considered urinary calci­um as a qualitative trait with hypercalciuria/normocalciuria as the only possible phenotypes. In these studies hypercalciuria inheritance was regarded as an autosomal dominant Mendelian trait with high penetrance. However, calcium excretion is a quantitative trait and its phenotypes are distrib­uted on a continuous scale. Variance of a quantitative trait is a multigenic parameter involving many alleles singularly ex­erting a small effect, and hypercalciuria has to be considered as a polygenic trait with a heterogeneous genetic substrate and complex pattern of hereditary transmission. we care about you health

The com­plexity of this picture is increased by gene-gene and gene-envi­ronment interactions with reciprocal influences, able to change substantially the effect of a gene on a phenotype. The search for genetics of hypercalciuria has been aimed to identify both candidate genes and genetic polymorphisms underlying the genetic susceptibility for this disorder. Although it cannot be excluded that polymorphisms in a single gene may be sufficient to cause hypercalciuria, it is more likely that PH arises when predisposing alleles, at different loci, together concur to regu­late urinary calcium excretion. The number of involved loci and the effect size of alleles may vary according to the role of can­didate genes in calcium metabolism, to the activity of their dif­ferent variants and to the gene/s-gene/s interactions. A different genetic substrate may be present in the two subpopula- tions of stone formers identified by the analysis of calcium ex­cretion distribution: they may be distinguished by the presence of allele variants at one locus or, more likely, at few loci having remarkable effects on the phenotype, shifting the mean of the calcium excretion distribution curve toward higher values. Genetic causes of PH have been approached with different strategies.


Genetics of primary hypercalciuria

Jul 6, 2011 Author: Walter Mcneil | Filed under: Disease

Genetics of primary hypercalciuria


Primary hypercalciuria (PH) is a multifactorial disorder whose onset depends both on environmental and genetic factors. As for other complex diseases, such as diabetes, hypertension, osteoporosis, molecular technologies will be helpful to identify either the responsible genetic factors or subjects susceptible to develop such disorders, providing the opportunity for ade­quate clinical management and therapy. PH is a complex highly heterogeneous defect of calcium metabolism character­ized by an elevated urinary excretion of calcium, in the ab­sence of other alterations. According to Frick and Bushinsky, it can be caused by a “dysregulation of calcium transport at sites where large fluxes of calcium must be precisely con­trolled: these sites are the intestine, kidney and bone”. Generally, it is defined by the occurrence of a urinary calcium excretion exceeding the threshold values, established in 1957 by Hodgkinson and Pyrah, at 7.5 mmol/24 hours for men and 6.25 mmol/24 hours for women. Alternatively, urinary calci­um may be normalized to body weight and hypercalciuria is considered as the calcium excretion above 100 mmol/24 hours per kg of body weight in both sexes. Hypercalciuric sub­jects represent the 5-10% of general population. Online Pharmacy 

Their presence causes a skewness to high values in the urinary cal­cium distribution curve, which is more evident in the stone forming (Figure 1) or osteoporotic populations. The frequency of hypercalciuria among these patients is higher than usually found in general population and may involve 20-50% of them. Analysis of the calcium excretion distribution curve in 471 stone formers indicates that it better fits a bimodal model (Figure 1). According to this model, stone formers appear to be composed by two different subsets of subjects. The first one is composed by 23% of patients, mostly hypercalciurics, whose calcium excretion can be estimated of 153±48 mmol/kg body weight in 24 hours. The other group, mainly composed by normocalciuric subjects, has an estimated calcium excre­tion of 85±33 mmol/kg body weight in 24 hours. Overlapping of calcium excretion curves, representing these subpopulations, reveals that PH may include subjects with different character­istics.


To our knowledge, the only previously detailed report on the density of HLA-D region antigens on alveolar macrophages is that of Campbell et al who studied HLA-DR. Our study confirms that levels of HLA-DR on alveolar macrophages in sarcoidosis are slightly increased compared with normal; and it also shows that levels are within the normal range in patients with nongranulomatous fibrosing lung dis­eases where lavage lymphocyte increases are much less common. However, we observed even more significant increases in levels of HLA-DQ and DP on alveolar macrophages in sarcoidosis. HLA-DQ and DP were also strikingly increased on alveolar macrophages in EAA, which is another granulomatous lung disease associated with strikingly increased numbers of T lymphocytes in lavage samples. Thus, we suggest that enhanced expression of HLA-D region antigens on alveolar macrophages, in particular HLA-DQ and DP, may be involved in the mechanisms leading to enhanced antigen-presenting function and T-cell pro­liferation within the lungs not only in sarcoidosis but also in EAA.




Most Popular

  • None found

Recent Comments

  • None found