Phenotype and genotype heterogeneity in autosomal dominant polycystic kidney disease

Ravine, David; Rg, Walker; Gibson, RN; Forrest, S. M.; Richards, R.I.; Friend, Kathryn; Sheffield, L. J.; Kincaid-Smith, P; Danks, D. M.

doi:10.1016/0140-6736(92)92503-8

Cited by 164 publications

(91 citation statements)

References 20 publications

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“…This direct interaction is consistent with the clinical observation that patients with mutations of either PKD1 or PKD2 develop an identical phenotype of renal and extrarenal disease (although a milder form of the disease results from mutations of PKD2) (20,21). Evidence for the involvement of a third genetic locus in PKD includes the existence of diseases that resemble PKD and for which genetic linkage to PKD1 or PKD2 has been excluded (22)(23)(24)(25).…”

Section: Discussionsupporting

confidence: 84%

Genomic Organization and Functional Analysis of Murine PKD2L1

Murakami

Ohba

et al. 2005

Journal of Biological Chemistry

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Mutations in genes that encode polycystins 1 or 2 cause polycystic kidney disease (PKD). Here, we report the genomic organization and functional expression of murine orthologue of human polycystin-2L1 (PKD2L1). The murine PKD2L1 gene comprises 15 exons in chromosome 19C3. Coexpression of PKD2L1 together with polycystin-1 (PKD1) resulted in the expression of PKD2L1 channels on the cell surface, whereas PKD2L1 expressed alone was retained within the endoplasmic reticulum (ER). This suggested that interaction between PKD1 and PKD2L1 is essential for PKD2L1 trafficking and channel formation. Deletion analysis at the cytoplasmic tail of PKD2L1 revealed that the coiled-coil domain was important for trafficking by PKD1. Mutagenesis within two newly identified ER retention signal-like amino acid sequences caused PKD2L1 to be expressed at the cell surface. This indicated that the coiled-coil domain was responsible for retaining PKD2L1 within the ER. Functional analysis of murine PKD2L1 expressed in HEK 293 cells was undertaken using calcium imaging. Coexpression of PKD1 and PKD2L1 resulted in the formation of functional cation channels that were opened by hypo-osmotic stimulation, whereas neither molecule formed functional channels when expressed alone. We conclude that PKD2L1 forms functional cation channels on the plasma membrane by interacting with PKD1. These findings raise the possibility that PKD2L1 represents the third genetic locus that is responsible for PKD.

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Section: Discussionsupporting

confidence: 84%

Genomic Organization and Functional Analysis of Murine PKD2L1

Murakami

Ohba

et al. 2005

Journal of Biological Chemistry

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“…11 The renal phenotypes are also similar, although PKD2 patients have milder disease and a lower incidence of hypertension. 10,12 Consistent with the sug- …”

supporting

confidence: 60%

“…11 The renal phenotypes are also similar, although PKD2 patients have milder disease and a lower incidence of hypertension. 10,12 Consistent with the sug-gestion that ADPKD proteins have related functions and similar systemic disease phenotypes, expression of PKD1 13 and PKD2 4 has been found in most human tissues. To date, however, the different cell types expressing these proteins have not been systematically defined.…”

mentioning

confidence: 61%

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

179

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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“…11,12 Even though all types of ADPKD present with an identical profile of extrarenal manifestations (including liver cysts and aneurysms), PKD1 is the most severe, with a lower median survival and a higher risk of progressing to endstage renal disease. 13,14 The PKD1 gene encodes a 14 kb mRNA that is derived from 46 exons that extend over B50 kb of genomic DNA. The PKD1 gene product, polycystin-1, is 4302 amino acids in length and is likely to be an integral membrane glycoprotein that may be involved in cell -cell or cell-matrix interactions.…”

Section: Introductionmentioning

confidence: 99%

Depletion of PKD1 by an antisense oligodeoxynucleotide induces premature G1/S-phase transition

et al. 2004

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Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of epithelial cells and the influx of cyst fluid. The 14-kb mRNA of the polycystic kidney disease gene, PKD1, encodes the polycystin-1 protein, whose function remains unknown. In this study, we observed that polycystin-1 localized in epithelial cell -cell contacts of 293 cells. We found, by bromodeoxyuridine (BrdU) incorporation experiments and Western blot analysis of S-phase-specific cyclins, that the depletion of polycystin-1 led to an increased cell proliferation rate and caused a premature G1/S-phase transition. In addition, we showed that the depletion of polycystin-1 reduced the amount of p53 in 293 cells irradiated by UV light, suggesting that polycystin-1 acts as a regulator of G1 checkpoint, which controls entry into the S phase and prevents the replication of damaged DNA. Our results might provide an insight into the formation and progression of ADPKD cysts.

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Phenotype and genotype heterogeneity in autosomal dominant polycystic kidney disease

Cited by 164 publications

References 20 publications

Genomic Organization and Functional Analysis of Murine PKD2L1

Genomic Organization and Functional Analysis of Murine PKD2L1

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

Depletion of PKD1 by an antisense oligodeoxynucleotide induces premature G1/S-phase transition

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