A Novel Claudin 16 Mutation Associated with Childhood Hypercalciuria Abolishes Binding to ZO-1 and Results in Lysosomal Mistargeting

Müller, Dominik; Kausalya, P. Jaya; Claverie-Martı́n, Félix; Meij, Iwan C.; Eggert, Paul; García‐Nieto, Victor; Hunziker, Walter

doi:10.1086/380418

Cited by 170 publications

(122 citation statements)

References 28 publications

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“…Various mutations of PCLN-1 within the extracellular loops or the transmembrane domains have been identified in patients with FHHNC (4,19,20). Recently, Muller et al (21) reported a novel mutation at the C-terminal Thr residue of the PDZ-binding motif that inhibits the association of PCLN-1 with ZO-1 in patients with idiopathic hypercalciuria. So far, biochemical and cell biological characterizations of the PDZ-binding motif of PCLN-1 have not been examined.…”

Section: Discussionmentioning

confidence: 99%

“…The deletion of the PDZ-binding motif (YV) at the C terminus of claudin-1-8 was enough to inhibit the association of claudins with ZO-1, but the mutants could be still distributed at the TJ (9). On the contrary, PCLN-1 mutants with the substitution of Thr for Arg at the C terminus led to lysosomal mistargeting (21). We found that PCLN-1 mutants can be incorporated in TJ to some extent without binding to ZO-1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Association of Paracellin-1 with ZO-1 Augments the Reabsorption of Divalent Cations in Renal Epithelial Cells

Ikari

Hirai

Shiroma

et al. 2004

Journal of Biological Chemistry

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Paracellin-1 (PCLN-1) belongs to the claudin family of tight junction proteins and possibly plays a critical role in the reabsorption of magnesium and calcium. So far, the physiological properties of PCLN-1 have not been clarified. In the present study, we investigated whether PCLN-1 is associated with ZO-1. We also investigated whether 45 Ca 2؉ transport across the paracellular barrier is affected by this association. In vitro binding analysis using glutathione S-transferase fusion protein showed that the C-terminal TRV sequence, especially Thr and Val residues, of PCLN-1 interacts with ZO-1. Next, PCLN-1 was stably expressed in Madin-Darby canine kidney cells using a FLAG tagging vector. ZO-1 was co-immunoprecipitated with the wild-type PCLN-1 and the alanine substitution (TAV) mutant. However, mutants of the deletion (⌬TRV) and the alanine substitution (ARV and TRA) inhibited the association of PCLN-1 with ZO-1. Confocal immunofluorescence demonstrated that the wild-type PCLN-1 and the TAV mutant localized in the tight junction along with ZO-1, but the ⌬TRV, ARV, and TRA mutants were widely distributed in the lateral membrane including the tight junction area. Interestingly, monolayers of cells expressing the wild-type PCLN-1 and the TAV mutant showed higher activities of 45 Ca 2؉ transport from apical to basal compartments, compared with those expressing the ⌬TRV, ARV, and TRA mutants and the mock cells. 45 Ca 2؉ transport was inhibited by increased magnesium concentration suggesting that magnesium and calcium were competitively transported by PCLN-1. It was noted that a positive electrical potential gradient enhanced 45 Ca 2؉ transport from apical to basal compartments without affecting the opposite direction of transport. Thus, PCLN-1 localizes to the tight junction followed by association with ZO-1, and the PCLN-1⅐ZO-1 complex may play an essential role in the reabsorption of divalent cations in renal epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association of Paracellin-1 with ZO-1 Augments the Reabsorption of Divalent Cations in Renal Epithelial Cells

Ikari

Hirai

Shiroma

et al. 2004

Journal of Biological Chemistry

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“…It contains a PDZ-binding motif that enables claudins to directly interact with the tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3 (53), with MUPP1 (40) and with PATJ (85). The interaction with cytoplasmic scaffolding proteins like ZO-1 indirectly links claudins to the actin cytoskeleton and most likely stabilizes them at the tight junction (77). The cytoplasmic tail upstream of the PDZ is required for targeting of claudins to the tight junctional complex (86) and a determinant of protein stability (105).…”

Section: Structure Of Claudinsmentioning

confidence: 99%

Biology of claudins

Angelow¹,

Ahlstrom²,

Yu³

2008

American Journal of Physiology-Renal Physiology

307

294

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Claudins are a family of tight junction membrane proteins that regulate paracellular permeability of epithelia, likely by forming the lining of the paracellular pore. Claudins are expressed throughout the renal tubule, and mutations in two claudin genes are now known to cause familial hypercalciuric hypomagnesemia with nephrocalcinosis. In this review, we discuss recent advances in our understanding of the physiological role of various claudins in normal kidney function, and in understanding the fundamental biology of claudins, including the molecular basis for selectivity of permeation, claudin interactions in tight junction formation, and regulation of claudins by protein kinases and other intracellular signals.

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“…Although renal features like nephrocalcinosis were reported in heterozygous carriers of a CLDN19 gene mutation, 11 we were unable to find reported families in which a heterozygous carrier showed to have an evident hypercalciuria and low normal magnesemia but no other disease symptoms. This findings alert on the need to carefully explore the FHHNC clinical, laboratory, kidney ultrasonography, and mutation status in first degree relatives of patients with CLDN19 gene mutations to avoid unsuitable kidney donors.…”

Section: Discussionmentioning

confidence: 76%

“…9 Mutations in CLDN16 and CLDN19 occur throughout the coding region and can affect proper folding, intracellular trafficking of the protein, or its paracellular pore forming function. [11][12][13] Herein, we present the first case report of a Mexican family with three affected sisters carrying a p.Gly20Asp mutation in CLDN19.…”

Section: +mentioning

confidence: 99%

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: variable phenotypic expression in three affected sisters from Mexican ancestry

et al. 2014

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Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal disease caused by mutations in genes for the tight junction transmembrane proteins Claudin-16 (CLDN16) and Claudin-19 (CLDN19). We present the first case report of a Mexican family with three affected sisters carrying a p.Gly20Asp mutation in CLDN19 whose heterozygous mother showed evident hypercalciuria and normal low magnesemia without any other clinical, laboratory, and radiological symptoms of renal disease making of her an unsuitable donor. The affected sisters showed variable phenotypic expression including age of first symptoms, renal urinary tract infections, nephrolithiasis, nephrocalcinosis, and eye symptoms consisting in retinochoroiditis, strabismus, macular scars, bilateral anisocoria, and severe myopia and astigmatism. End stage renal disease due to renal failure needed kidney transplantation in the three of them. Interesting findings were a heterozygous mother with asymptomatic hypercalciuria warning on the need of carefully explore clinical, laboratory, kidney ultrasonograpy, and mutation status in first degree asymptomatic relatives to avoid inappropriate kidney donors; an evident variable phenotypic expression among patients; the identification of a mutation almost confined to Spanish cases and a 3.5 Mb block of genomic homozygosis strongly suggesting a common remote parental ancestor for the gene mutation reported.

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A Novel Claudin 16 Mutation Associated with Childhood Hypercalciuria Abolishes Binding to ZO-1 and Results in Lysosomal Mistargeting

Cited by 170 publications

References 28 publications

Association of Paracellin-1 with ZO-1 Augments the Reabsorption of Divalent Cations in Renal Epithelial Cells

Association of Paracellin-1 with ZO-1 Augments the Reabsorption of Divalent Cations in Renal Epithelial Cells

Biology of claudins

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: variable phenotypic expression in three affected sisters from Mexican ancestry

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