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Science 2 July 1999:
Vol. 285. no. 5424, pp. 103 - 106
DOI: 10.1126/science.285.5424.103
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Reports

Paracellin-1, a Renal Tight Junction Protein Required for Paracellular Mg2+ Resorption

David B. Simon, 12* Yin Lu, 12* Keith A. Choate, 12 Heino Velazquez, 2 Essam Al-Sabban, 3 Manuel Praga, 4 Giorgio Casari, 5 Alberto Bettinelli, 6 Giacomo Colussi, 7 Juan Rodriguez-Soriano, 8 David McCredie, 9 David Milford, 10 Sami Sanjad, 11 Richard P. Lifton 12dagger

Epithelia permit selective and regulated flux from apical to basolateral surfaces by transcellular passage through cells or paracellular flux between cells. Tight junctions constitute the barrier to paracellular conductance; however, little is known about the specific molecules that mediate paracellular permeabilities. Renal magnesium ion (Mg2+) resorption occurs predominantly through a paracellular conductance in the thick ascending limb of Henle (TAL). Here, positional cloning has identified a human gene, paracellin-1 (PCLN-1), mutations in which cause renal Mg2+ wasting. PCLN-1 is located in tight junctions of the TAL and is related to the claudin family of tight junction proteins. These findings provide insight into Mg2+ homeostasis, demonstrate the role of a tight junction protein in human disease, and identify an essential component of a selective paracellular conductance.

1 Howard Hughes Medical Institute, Department of Genetics,
2 Department of Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
3 Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
4 Servicio de Nefrologia, Hospital 12 de Octubre, Madrid, Spain.
5 Telethon Institute of Genetics and Medicine, Milan 20132, Italy.
6 Department of Pediatrics II, University of Milan, Milan, Italy.
7 Renal Division, Niguarda "Ca' Granda" Hospital, Milan, Italy.
8 Department of Pediatrics, Hospital de Cruces, Baracaldo E-48903, Spain.
9 Department of Nephrology, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia.
10 Department of Nephrology, Birmingham Children's Hospital, Birmingham B16 8ET, UK.
11 Department of Pediatrics, American University, Beirut, Lebanon.
*   These authors contributed equally to this report.

dagger    To whom correspondence should be addressed. E-mail: richard.lifton{at}yale.edu

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Dynamic behavior of paired claudin strands within apposing plasma membranes.
H. Sasaki, C. Matsui, K. Furuse, Y. Mimori-Kiyosue, M. Furuse, and S. Tsukita (2003)
PNAS 100, 3971-3976
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Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells.
S. Amasheh, N. Meiri, A. H. Gitter, T. Schoneberg, J. Mankertz, J. D. Schulzke, and M. Fromm (2003)
J. Cell Sci. 115, 4969-4976
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Exclusion of mutations in FXYD2, CLDN16 and SLC12A3 in two families with primary renal Mg2+ loss.
I. C. Meij, L. P. W. J. van den Heuvel, S. Hemmes, W. A. van der Vliet, J. L. Willems, L. A. H. Monnens, and N. V. A. M. Knoers (2003)
Nephrol. Dial. Transplant. 18, 512-516
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Recent Advances in Molecular Genetics of Hereditary Magnesium-Losing Disorders.
M. Konrad and S. Weber (2003)
J. Am. Soc. Nephrol. 14, 249-260
   Abstract »    Full Text »    PDF »
Cell Junction Dynamics in the Testis: Sertoli-Germ Cell Interactions and Male Contraceptive Development.
C. Y. Cheng and D. D. Mruk (2002)
Physiol Rev 82, 825-874
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Phospholipase C-gamma Modulates Epithelial Tight Junction Permeability through Hyperphosphorylation of Tight Junction Proteins.
P. D. Ward, R. R. Klein, M. D. Troutman, S. Desai, and D. R. Thakker (2002)
J. Biol. Chem. 277, 35760-35765
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Developmental changes in rabbit proximal straight tubule paracellular permeability.
R. Quigley and M. Baum (2002)
Am J Physiol Renal Physiol 283, F525-F531
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Abnormal regulation of ENaC: syndromes of salt retention and salt wasting by the collecting duct.
J. A. Schafer (2002)
Am J Physiol Renal Physiol 283, F221-F235
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