Polycystin:<i>In vitro</i>synthesis,<i>in vivo</i>tissue expression, and subcellular localization identifies a large membrane-associated protein

Ibraghimov‐Beskrovnaya, Oxana; Dackowski, William; Foggensteiner, Lukas; Coleman, Nicholas; Thiru, S; Petry, Linda R.; Burn, Timothy C.; Connors, Timothy D.; Raay, Terence J. Van; Bradley, John R.; Qian, Fang; Onuchic, Luiz Fernando; Watnick, Terry; Piontek, Klaus; Hakim, Raymond M.; Landes, Gregory M.; Germino, Gregory G.; Sandford, Richard; Klinger, Katherine W.

doi:10.1073/pnas.94.12.6397

Cited by 189 publications

(169 citation statements)

References 31 publications

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“…Apart from the study of Griffin et al 27 that observed no polycystin-1 expression in the adult, this later distal expression pattern persisting into adult life has been observed in several other studies. 20,28,29 The expression of the ADPKD proteins appears only weakly in the earliest nephrogenic precursors, and is consistent with data from the Pkd1 Ϫ/Ϫ knockout mouse, 30 where formation of the nephron appears to occur normally; the role of these proteins is thus probably in tubular elongation and the maintenance of tubular architecture rather than in epithelial induction.…”

Section: Discussionsupporting

confidence: 71%

“…We previously described the highest levels of adult PKD1 gene expression in the brain. 13 Unlike others, 29 we did not observe polycystin-1 (or polycystin-2) expression by astrocytes, but rather by neuronal cell bodies throughout the developing brain. However, no neural phenotype has been reported for ADPKD, indicating that the presence of one mutant allele does not disrupt neural development.…”

Section: Discussionmentioning

confidence: 69%

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Coordinate Expression of the Autosomal Dominant Polycystic Kidney Disease Proteins, Polycystin-2 And Polycystin-1, in Normal and Cystic Tissue

Ong

Ward

Butler

et al. 1999

The American Journal of Pathology

176

151

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A second gene for autosomal dominant polycystic kidney disease (ADPKD) , PKD2, has been recently identified. Using antisera raised to the human PKD2 protein , polycystin-2 , we describe for the first time its distribution in human fetal tissues , as well as its expression in adult kidney and polycystic PKD2 tissues. Its expression pattern is correlated with that of the PKD1 protein , polycystin-1. In normal kidney, expression of polycystin-2 strikingly parallels that of polycystin-1 , with prominent expression by maturing proximal and distal tubules during development, but with a more pronounced distal pattern in adult life. In nonrenal tissues expression of both polycystin molecules is identical and especially notable in the developing epithelial structures of the pancreas, liver , lung , bowel , brain , reproductive organs, placenta , and thymus. Of interest , nonepithelial cell types such as vascular smooth muscle , skeletal muscle , myocardial cells , and neurons also express both proteins. In PKD2 cystic kidney and liver , we find polycystin-2 expression in the majority of cysts, although a significant minority are negative , a pattern mirrored by the PKD1 protein. The continued expression of polycystin-2 in PKD2 cysts is similar to that seen by polycystin-1 in PKD1 cysts , but contrasts with the reported absence of polycystin-2 expression in the renal cysts of Pkd2؉/؊ mice. These results suggest that if a two-hit mechanism is required for cyst formation in PKD2 there is a high rate of somatic missense mutation. The coordinate presence or loss of both polycystin molecules in the same cysts supports previous experimental evidence that hetero- Renal cysts are the primary cause of morbidity in autosomal dominant polycystic kidney disease (ADPKD) but it is evident that the disease phenotype extends beyond the kidney. Cysts are commonly found in the liver and pancreas and have been reported in testis, spleen, ovary, uterus, esophagus, and brain. Moreover, abnormalities suggestive of a generalized disorder of connective tissue, including cardiac valvular abnormalities (especially mitral valve prolapse), intracranial berry aneurysms, colonic diverticulae, inguinal hernia, and a family with Marfanoid habitus, have been described. 1,2 Mutations in two genes, PKD1 and PKD2, account for the vast majority of patients with ADPKD. The identification of these genes 3,4 has thus provided a new opportunity to study the pathophysiology of ADPKD. The predicted proteins appear quite different in structure (the PKD1 protein, polycystin-1, is ϳ4 times larger than its counterpart, polycystin-2 4,5 ). Nonetheless, they share a significant region of homology in their transmembrane regions, an area also similar to a family of voltage-gated calcium/sodium channels. 4,6 Recent evidence indicates that the ADPKD proteins may interact in experimental systems. 7,8 PKD2 is less prevalent than PKD1, accounting for ϳ15% of ADPKD cases, 9,10 but preliminary evidence suggests they share the same spectrum of extrarenal manifestations. In one st...

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 69%

Coordinate Expression of the Autosomal Dominant Polycystic Kidney Disease Proteins, Polycystin-2 And Polycystin-1, in Normal and Cystic Tissue

Ong

Ward

Butler

et al. 1999

The American Journal of Pathology

176

151

View full text Add to dashboard Cite

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“…In ADPKD patients, expression levels of the PKD1/PKD2 mutated allele can be strongly or mildly reduced. Paradoxically, PKD1/PKD2 and PC1/PC2 are found overexpressed in human ADPKD kidneys (3,(62)(63)(64)(65)(66)(67). The severity of the ADPKD cystogenic mechanism(s) is likely to depend on modulation of the remaining non-mutant copy of PKD1/PKD2 potentially through de novo mutations, a stochastic event, altered functional role of polycystins and/or epigenetic inheritance that are actively under study.…”

Section: Upregulation Of C-myc In Human Adpkdmentioning

confidence: 99%

c-Myc Signalling in the Genetic Mechanism of Polycystic Kidney Disease

Trudel

2015

Polycystic Kidney Disease

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Licence: This open access article is licenced under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the author and the publisher are explicitly identified and properly acknowledged as the original source. AbstractThe Myc family of transcription factors regulates major biological processes such as proliferation, stem/progenitor cell pluripotency, metabolism, apoptosis, cell growth and differentiation. The most-studied member c-Myc is essential in embryonic development and cellular homeostasis. Dysregulation of c-Myc protein function is not only associated with malignant transformation and human tumors but is also implicated in autosomal dominant polycystic kidney disease (ADPKD), a human genetic disorder, considered a neoplasia in disguise. Studies from human ADPKD kidneys, caused by mutation in the

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“…On the other hand, there is also evidence that the majority of cysts show strong immunoreactivity with antibodies directed against both polycystins. [13][14][15][16] The aim of this study was to search for LOH in microsatellites linked to PKD1 and PKD2 genes and the chromosome 3 marker which is frequently deleted in some tumors 7 in epithelial cystic cells from ADPKD patients. We have analysed 211 renal and hepatic cysts from seven different patients for LOH, and have detected a 13.3% LOH for PKD1.…”

Section: Introductionmentioning

confidence: 99%

Loss of heterozygosity in renal and hepatic epithelial cystic cells from ADPKD1 patients

et al. 2000

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Autosomal dominant polycystic kidney disease (ADPKD) is one of the commonest genetic diseases in man, affecting 1:1000 individuals in the Caucasian population. It is caused by mutations in the PKD1 or PKD2 genes. Recently, controversial data regarding the mutational mechanism underlying cyst initiation have been reported: genetic analyses have shown that second somatic mutations may lead to cyst formation (detected as microsatellite loss of heterozygosity, LOH, and point mutations), but immunohistochemical studies show strong immunoreactivity for polycystin in some cysts. In order to further characterise this matter we have analysed 211 cysts from seven different patients for LOH, we have detected a 13.3% LOH for PKD1. This loss was specific to PKD1 as no LOH was detected when other chromosomal regions were studied. Whenever linkage analysis has been possible, it has been proved that the lost allele corresponded to the wild-type. Our data supports previous results in the two-hit theory for ADPKD due to the large number of cysts studied. ADPKD would occur through a recessive cellular mechanism. The probability of cyst development would depend on the probability of mutation in the second allele. The different phenotypical expression of the same mutation reported in ADPKD could be due to the different tendency of inactivation in the second allele in each individual.

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Polycystin:In vitrosynthesis,in vivotissue expression, and subcellular localization identifies a large membrane-associated protein

Cited by 189 publications

References 31 publications

Coordinate Expression of the Autosomal Dominant Polycystic Kidney Disease Proteins, Polycystin-2 And Polycystin-1, in Normal and Cystic Tissue

Coordinate Expression of the Autosomal Dominant Polycystic Kidney Disease Proteins, Polycystin-2 And Polycystin-1, in Normal and Cystic Tissue

c-Myc Signalling in the Genetic Mechanism of Polycystic Kidney Disease

Loss of heterozygosity in renal and hepatic epithelial cystic cells from ADPKD1 patients

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