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.

This raised the question as to whether mutations in CLCN5 gene might contribute to the phenotype in patients with the diagnosis of PH, a condition that is twice as common in males as in females suggesting that a subset of pa­tients may have an X-linked transmission. Scheinmann et al. looked for CLCN5 gene mutations in a group of 32/107 un­related individuals (82 adults and 25 children) with PH. However, PH was defined in a broad sense; this is meaningful in the Dent’s condition where the mechanism of hypercalciuria includes both excessive intestinal absorption of dietary calcium and fast­ing hypercalciuria. No CLCN5 gene mutation was observed in this study and it is likely that Dent’s disease accounts for no more than 3% of patients with sporadic form of PH. Gambaro et al. recently performed CLCN5 gene mutation analysis in dia- lyzed patients with a personal history of calcium or radiopaque stones and found no case of Dent’s disease confirming that this disorder is really rare even in the pool of patients in which it should be over-represented (Gambaro et al., unpublished).