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.

Sequencing analysis identified an inactivating mutation with substitution of phenylalanine to leucine at codon 881, located in the cytoplasmic tail of the receptor and functional studies demonstrated an inactivation of the receptor, probably with a different functional capacity, in parathyroid and renal cells, determining a more severe derangement in extracellular Ca2+-sensing in the former. The hypothesis of implica­tion of the CaSR gene in absorptive hypercalciuria (AH) and calcium renal stones derives from the possibility that a mild activation of the C a S R could cause (in association with mild hypocalcaemia) both the increased intestinal calcium absorp­tion and calcium renal loss. Recently, a mechanism described by Hebert et al (40) suggests that when at basolateral level calcium concentrations are elevated, condition minimizing the reabsorption, C a S R activation induces the inhibition of the Na+/K+/Cl co-transporter, then inhibiting the electric force gra­dient driving the paracellular transportation of Ca2+ from lumen to blood. However, association studies in general popula­tions have not corroborated this hypothesis. Indeed, Petrucci et al in a sib-pairs analysis in 359 French-Canadian stone former subjects showed no significant association between genetic variants of the CaSR gene and PH and ICN traits. Fur­thermore, Lerolle et al. failed to detect any mutation in the seven coding exons of the CaSR gene in 9 families with PH, renal stones and with a familial transmission consisting of au- tosomal dominant inheritance. It is not possible to rule out that mutations of the CaSR gene could be found in some other families or other populations, or that mutations of regulatory regions of the gene may exist; nevertheless these findings in­dicate that C a S R gene mutations do not represent a common cause of familial PH. More recently, Vezzoli et al. in an Italian population case-control study, analyzing three clustered Single Nucleotide Polymorphisms (SNPs) at exon 7 of CaSR (G/T at codon 986, G/A at codon 990, and C/G at codon 1011), hypothesized a role for such variants in the physiologi­cal regulation of the C a S R gene transcription levels, thus identifying patients with increased relative risk for hypercalci- uria/renal stones, according to specific clinical-biochemical phenotypes. Such SNPs determine non-conservative amino acid changes, which functional effects are still unknown, al­though the importance of the allele 986Ser and ofthe allele 990Gly has been previously suggested according to lower plasma levels of calcium in healthy people and of PTH in uremic patients, respectively. Thus, Vezzoli et al. suggested that the 990Gly allele may increase the CaSR sen­sitivity or response to calcium ions, increasing inhibition of PTH secretion, leading to lower calcium serum levels, in­creased calciuria and bone turnover. According to this hypoth­esis, this gene variant should correspond to an activating SNP. However, CaSR gene cannot be considered as a major gene involved in the pathogenesis of PH, representing only one of the genetic components modulating the calcium excre­tion. The minor contribution of the C a S R gene to calcium ex­cretion could explain why no linkage was shown in the sib-pair study carried out in Canada.