Disease relevance of CLDN16

• Mutations in the CLDN16 gene were found to underlie autosomal recessive hypomagnesaemia associated with hypercalciuria and nephrocalcinosis [1].
• Paracellin-1 is a member of the tight junction claudin protein family and mutations in the paracellin-1 gene cause a human hereditary disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) with severe renal Mg2+ wasting [2].
• CONCLUSIONS: We propose that mutations in CLDN16 are considered in childhood hypocalcemia [3].
• 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 [4].
• In 13 of 23 families, hypercalciuria and/or nephrolithiasis were observed in otherwise unaffected family members, indicating a possible role of heterozygous PCLN-1 mutations in yielding hypercalciuric stone-forming conditions [5].

High impact information on CLDN16

• Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption [6].
• Here, positional cloning has identified a human gene, paracellin-1 (PCLN-1), mutations in which cause renal Mg2+ wasting [6].
• Over 20 different mutations in the CLDN16 gene have been identified in patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), a disease of excessive renal Mg2+ and Ca2+ excretion [7].
• Claudin-16 (Cldn16) is selectively expressed at tight junctions (TJs) of renal epithelial cells of the thick ascending limb of Henle's loop, where it plays a central role in the reabsorption of divalent cations [7].
• Nine of the 21 Cldn16 mutants we characterized were retained in the endoplasmic reticulum, where they underwent proteasomal degradation [7].

Chemical compound and disease context of CLDN16

• CONTEXT: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is caused by a dysfunction of Claudin-16 (CLDN16) and characterized by renal wasting of Mg(2+) and Ca(2+) [3].
• BACKGROUND: Hydrochlorothiazide (HCT) is applied in the therapy of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) caused by claudin-16 (CLDN16) mutation [8].
• Mutations in the gene coding for the renal tight junction protein claudin 16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, an autosomal recessive disorder of renal Ca(2+) and Mg(2+) handling that progressively leads to chronic renal failure, with nephrolithiasis having been reported in heterozygous carriers [9].
• An Unusual Patient with Hypercalciuria, Recurrent Nephrolithiasis, Hypomagnesemia and G227R Mutation of Paracellin-1. An Unusual Patient with Hypercalciuria and Hypomagnesemia Unresponsive to Thiazide Diuretics [10].

Biological context of CLDN16

• Thus, mutations at different intragenic sites in the claudin 16 gene may lead to particular clinical phenotypes with a distinct prognosis [9].
• Genotype analysis revealed PCLN-1 mutations in all except three mutant alleles (94%) [5].
• Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis maps to chromosome 3q27 and is associated with mutations in the PCLN-1 gene [11].
• Extensive total-genome haplotype analysis revealed homozygosity in one family, in the region of the PCLN1 gene [12].
• Blocking clathrin-mediated endocytosis increases surface expression of Cldn16 L203X [13].

Anatomical context of CLDN16

• Paracellin-1 and the modulation of ion selectivity of tight junctions [2].
• The presence of membrane-lined channels that cross the syncytiotrophoblast constituting a paracellular pathway has been determined by transmission electron microscopy and by the co-immunolocalization of claudin 16 with the plasma membrane proteins Na(+)K(+)-ATPase and GP135 [14].
• We have unexpectedly found that, in normal placentae, the multinucleated syncytiotrophoblast layer displays claudin 4 at the basal surface of the plasma membrane, and claudin 16 along the apical and basolateral surfaces [14].
• In contrast to wild-type claudin 16, the mutant no longer localizes to tight junctions in kidney epithelial cells but instead accumulates in lysosomes [9].
• Isolated hereditary renal magnesium (Mg) wasting may result from mutations in the renal tubular epithelial cell tight junction protein paracellin-1 gene or the tubular Na(+),K(+)-ATPase gamma-subunit gene FXYD2 [15].

Associations of CLDN16 with chemical compounds

• We hypothesize that in the thick ascending limb of the nephron, paracellin-1 dysfunction, with a concomitant loss of cation selectivity, could contribute to the dissipation of the lumen-positive potential that is the driving force for the reabsorption of Mg2+ [2].
• Since claudin 16 functions as a paracellular channel for Mg(2+), its diffuse pattern in preeclamptic placentae suggests the altered paracellular transport of Mg(2+) between the maternal blood and the placental tissue [14].
• Hydrochlorothiazide in CLDN16 mutation [8].
• The degradation of dephosphorylated PCLN-1 and S217A mutant was inhibited by chloroquine, a specific lysosome inhibitor [16].
• PKA inhibitors, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-89) and myristoylated protein kinase A inhibitor 14-22 amide PKI, and an adenylate cyclase inhibitor, 2',5'-dideoxy adenosine (DDA), reduced the phosphoserine level of PCLN-1 [16].

Other interactions of CLDN16

• Heteroduplex analysis and DNA sequencing of coding regions and exon/intron boundaries of two genes (CLDN16 and FGF12) in this interval did not reveal disease-causing mutations [17].
• No mutations were found in CLDN16 and SLC12A3 either [1].
• Exclusion of mutations in FXYD2, CLDN16 and SLC12A3 in two families with primary renal Mg2+ loss [1].
• Inherited hypercalciuric syndromes: Dent's disease (CLC-5) and familial hypomagnesemia with hypercalciuria (paracellin-1) [18].

Analytical, diagnostic and therapeutic context of CLDN16

• Mouse multiple-tissue Northern blot showed Pcln1 expression exclusively in the kidney [19].
• The identification and characterization of the rodent Pcln1 genes provide the basis for further studies of paracellin-1 function in suitable animal models [19].
• Cldn-16 transcripts were also identified by RT-PCR [20].
• As the first step to clarify these roles, we examined the expression and distribution of claudin-16 and several other major claudin subtypes, claudins 1-4 and 10, in bovine renal tubular segments by immunofluorescence microscopy [21].
• Immunofluorescent studies of renal sections showed significant increase in calbindin-D28k (238 +/- 10%) and TRPV5 (211 +/- 10%), but no changes in paracellin-1 in Western blotting (cortex: 110 +/- 7%; medulla: 99 +/- 7%) [22].

References