A Deletion of the Paracellin-1 Gene Is Responsible for Renal Tubular Dysplasia in Cattle

Ohba, Yasunori; Kitagawa, Hitoshi; Kitoh, Katsuya; Sasaki, Yoshihide; Takami, Marika; Shinkai, Yusuke; Kunieda, Tetsuo

doi:10.1006/geno.2000.6298

Cited by 80 publications

(55 citation statements)

References 23 publications

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“…Claudin-16/paracellin-1 was first identified as the prod- uct of the gene (CLDN16/PCLN1) responsible for FHHNC in humans [27] followed by the observation that renal tubular dysplasia in cattle was linked to deleterious mutations of the CLDN16 gene [9,20]. Although the significance of claudin-16 function in Mg 2+ and Ca 2+ metabolism remains uncertain in cattle [21], the affected animals [24] and FHHNC patients [35] share several histopathological findings, including tubular atrophy, immature tubules, and interstitial fibrosis.…”

Section: Claudins Expressed In Tal Of Henle's Loopmentioning

confidence: 99%

“…Since FHHNC has been characterized by renal Mg 2+ and Ca 2+ wasting, claudin-16 is likely to form aqueous pores that function as the paracelluar pathway for Mg 2+ and Ca 2+ in claudin-based TJs [3,27]. A recent report by Hou et al [11] clearly demonstrated that claudin-16/ paracellin-1 modulated the ion selectivity of the TJ by selectively increasing the permeability of Na + with no effect on Cl -when transfected into LLC-PK1 epithelial cells, and suggested that a loss of claudin-16/paracellin-1 function in the TAL could lead to losing the lumen-positive potential as the driving force for the reabsorption of Mg 2+ .Claudin-16 is also responsible for renal tubular dysplasia with interstitial nephritis in Japanese black cattle [9,20]. This disease is inherited in an autosomal recessive mode and characterized by renal failure, growth retardation, and early death due to renal dysfunction with a high incidence.…”

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confidence: 99%

“…Claudin-16 is also responsible for renal tubular dysplasia with interstitial nephritis in Japanese black cattle [9,20]. This disease is inherited in an autosomal recessive mode and characterized by renal failure, growth retardation, and early death due to renal dysfunction with a high incidence.…”

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confidence: 99%

“…Interestingly, in contrast to FHHNC, decreases in serum Mg 2+ and Ca 2+ concentrations are not apparent in cattle with claudin-16 deficiency, while a reduction in renal reabsorption rate has been suggested for Mg 2+ [21]. This suggests that there is a compensatory system(s) for metabolism of these divalent cations in the absence of claudin-16 or that bovine claudin-16 may have functions in paracellular transport of Mg 2+ and Ca 2+ distinct from those of the human counterpart despite their high homology in amino acid sequences [9,20].…”

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Restricted Localization of Claudin-16 at the Tight Junction in the Thick Ascending Limb of Henle's Loop Together with Claudins 3, 4, and 10 in Bovine Nephrons

et al. 2006

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ABSTRACT. Claudin-16 is one of the tight junction protein claudins and has been shown to contribute to reabsorption of divalent cations in the human kidney. In cattle, total deficiency of claudin-16 causes severe renal tubular dysplasia without aberrant metabolic changes of divalent cations, suggesting that bovine claudin-16 has some roles in renal tubule formation and paracellular transport that are somewhat different from those expected from the pathology of human disease. 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. Claudin-16 was exclusively distributed to the tight junction in the tubular segment positive for TammHorsfall glycoprotein, the thick ascending limb (TAL) of Henle's loop, and was found colocalized with claudins 3, 4, and 10. This study also demonstrates that bovine kidneys possess segment-specific expression patterns for claudins 2-4 and 10 that are different from those reported for mice. Particularly, distribution of claudin-4 in the TAL and distal convoluted tubules was characteristic of bovine nephrons as were differences in the expression patterns of claudins 2 and 3. These findings demonstrate that the total lack of claudin-16 in the TAL segment is the sole cause of renal tubular dysplasia in cattle and suggest that the tight junctions in distinct tubular segments including the TAL have barrier functions in paracellular permeability that are different among animal species. KEY WORDS: cattle, claudin-16, paracellular pathway, renal tubule, tight junction.J. Vet. Med. Sci. 68 (5): [453][454][455][456][457][458][459][460][461][462][463] 2006 Tight junctions (TJs) are located at the apicalmost region of lateral membranes of epithelial cells, and play a central role in sealing the intercellular space in epithelial cellular sheets. TJs create the primary barrier to the diffusion of solutes and water through the paracellular pathway and maintain cell polarity as a boundary between the apical and basolateral plasma membrane domains [7,26,29,34]. On freeze-fracture electron microscopy, TJs are visualized as a continuous anastomosing network of intramembranous particle strands, i.e., TJ strands, and complementary grooves [28]. The major components of TJ strands are the integral membrane proteins occludin and claudins, all of which have four transmembrane spans and two intervening extracellular loops [19]. Claudins consist of a family of more than 20 homologous subtypes, and they show tissue-specific and segment-specific distribution patterns in epithelia [19,29] such as those of the gastrointestinal tract [23] and renal tubules [15].Among these claudin proteins, claudin-16, formerly paracellin-1, has been shown to be responsible for inherited disease. Various mutations of the CLDN16 gene were reported to be the cause for familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) in the human [27]. Simon...

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Section: Claudins Expressed In Tal Of Henle's Loopmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Restricted Localization of Claudin-16 at the Tight Junction in the Thick Ascending Limb of Henle's Loop Together with Claudins 3, 4, and 10 in Bovine Nephrons

et al. 2006

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“…Interestingly, there is a second inframe start codon within a suitable Kozak consensus sequence at position Met71, which is analogous to all other claudins. Sequence comparison of the human cDNA with other species and the results of mutation analysis suggest that the second translation initiation start site is used in vivo (33,39,40).…”

Section: Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinmentioning

confidence: 99%

Recent Advances in Molecular Genetics of Hereditary Magnesium-Losing Disorders

Konrad¹,

Weber²

2003

Journal of the American Society of Nephrology

111

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Abstract. Recent advances in molecular genetics in hereditary hypomagnesemia substantiated the role of a variety of genes and their encoded proteins in human magnesium transport mechanisms. This knowledge on underlying genetic defects helps to distinguish different clinical subtypes and gives first insight into molecular components involved in magnesium transport. By mutation analysis and functional protein studies, novel pathophysiologic aspects were elucidated. For some of these disorders, transgenic animal models were generated to study genotype-phenotype relations and disease pathology. This review will discuss genetic and clinical aspects of familial disorders associated with magnesium wasting and focuses on the recent progress that has been made in molecular genetics. Besides isolated renal forms of hereditary hypomagnesemia, the following disorders will also be presented: familial hypomagnesemia with hypercalciuria and nephrocalcinosis, hypomagnesemia with secondary hypocalcemia, Ca 2ϩ /Mg 2ϩ -sensing receptor-associated disorders, and disorders associated with renal salt-wasting and hypokalemic metabolic alkalosis, comprising the Gitelman syndrome and the Bartter-like syndromes.

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