The Diagnosis and Prognosis of Autosomal Dominant Polycystic Kidney Disease

Parfrey, Patrick S.; Bear, J. C.; Morgan, J.G.; Cramer, B.; McManamon, P J; Gault, M. H.; Churchill, David; Singh, Manjeet; Hewitt, Ross G.; Somlo, Stefan

doi:10.1056/nejm199010183231601

Cited by 326 publications

(154 citation statements)

References 32 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: 70%

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: 70%

Genomic Organization and Functional Analysis of Murine PKD2L1

Murakami

Ohba

et al. 2005

Journal of Biological Chemistry

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“…Other manifestations of this disorder, such as cyst formation in non-renal organs, cardiac valvular defects, colonic diverticulosis, and intracranial arterial aneurysms, accompany the renal disease variably. Linkage studies in ADPKD families have documented genetic heterogeneity (3,4), and at least two disease genes (PKD1 [MIM 601313] on chromosome 16p13.3 and PKD2 [MIM 173910] on chromosome 4q13-23) have been identified and characterized (5)(6)(7). A rare putative third disease gene (PKD3 [MIM 600666]) has been implicated by the identification of a small number of families unlinked to the known gene loci (8,9).…”

mentioning

confidence: 99%

Genotype-Renal Function Correlation in Type 2 Autosomal Dominant Polycystic Kidney Disease

Magistroni

He²,

Wang³

et al. 2003

Journal of the American Society of Nephrology

126

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Abstract. Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Mutations of two genes, PKD1 and PKD2, account for the disease in approximately 80 to 85% and 10 to 15% of the cases, respectively. Significant interfamilial and intrafamilial renal disease variability in ADPKD has been well documented. Locus heterogeneity is a major determinant for interfamilial disease variability (i.e., patients from PKD1-linked families have a significantly earlier onset of ESRD compared with patients from PKD2-linked families). More recently, two studies have suggested that allelic heterogeneity might influence renal disease severity. The current study examined the genotype-renal function correlation in 461 affected individuals from 71 ADPKD families with known PKD2 mutations. Fifty different mutations were identified in these families, spanning between exon 1 and 14 of PKD2. Most (94%) of these mutations were predicted to be inactivating. The renal outcomes of these patients, including the age of onset of end-stage renal disease (ESRD) and chronic renal failure (CRF; defined as creatinine clearance Յ 50 ml/min, calculated using the Cockroft and Gault formula), were analyzed. Of all the affected individuals clinically assessed, 117 (25.4%) had ESRD, 47 (10.2%) died without ESRD, 65 (14.0%) had CRF, and 232 (50.3%) had neither CRF nor ESRD at the last follow-up. Female patients, compared with male patients, had a later mean age of onset of ESRD (76.0 [95% CI, 73.8 Linear regression and renal survival analyses revealed that the location of PKD2 mutations did not influence the age of onset of ESRD. However, patients with splice site mutations appeared to have milder renal disease compared with patients with other mutation types (P Ͻ 0.04 by log rank test; adjusted for the gender effect). Considerable renal disease variability was also found among affected individuals with the same PKD2 mutations. This variability can confound the determination of allelic effects and supports the notion that additional genetic and/or environmental factors may modulate the renal disease severity in ADPKD.

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“…Gene locus effect is a major determinant for interfamilial disease variability: patients from PKD1-linked families have a much earlier onset of ESRD than patients from PKD2-linked families (median age, 53 [95% confidence interval (CI), 51.2 to 54.8] vs. 69 [95% CI, 66.9 to 71.3] years) (6,7). A gender effect on renal survival (i.e., absence of ESRD) favoring the female patients is also evident in type 2 but in not type 1 ADPKD (7)(8)(9).…”

mentioning

confidence: 99%

Progressive Loss of Renal Function Is an Age-Dependent Heritable Trait in Type 1 Autosomal Dominant Polycystic Kidney Disease

Paterson

Magistroni

et al. 2005

Journal of the American Society of Nephrology

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Significant intrafamilial phenotypic variability is well documented in autosomal dominant polycystic kidney disease (AD-PKD) and suggests a modifier effect. In this study, variance components analysis was performed to estimate the contribution of genetic factors for within-family renal disease variability in 406 patients from 66 type 1 ADPKD families. Overall, 39% of the study patients had ESRD at their last follow-up, and their renal survival did not differ by gender (P ‫؍‬ 0.35, log-rank test). Because their frequency plot of creatinine clearance (Ccr) assumed a bimodal distribution with a marked kurtosis that was not improved by transformations, the study cohort was decomposed into two separate groups (non-ESRD [n ‫؍‬ 247] and ESRD [n ‫؍‬ 159]) in which the Ccr plots were normally distributed. The heritability (h 2 ) of Ccr and age at ESRD (age ESRD ) and the genetic correlations between these measures and their covariates were estimated. In patients without ESRD, a significant heritability was found for Ccr (h 2 ‫؍‬ 0.42; P ‫؍‬ 0.0015) after adjusting for age (P ‫؍‬ 0.0001), systolic BP (P ‫؍‬ 0.0006), and treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (P ‫؍‬ 0.00001). Birth year, gender, BMI, diastolic and mean BP, and pack-years of cigarette smoking did not significantly influence the heritability of this trait. In patients with ESRD, age ESRD provides a better measure than Ccr, which was very narrowly distributed. A significant heritability was found for age ESRD (h 2 ‫؍‬ 0.78; P ‫؍‬ 0.00009) in these latter patients. None of the above covariates influenced the heritability of this trait. It is concluded that a significant modifier gene effect influences the progression of renal disease in type 1 ADPKD.

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The Diagnosis and Prognosis of Autosomal Dominant Polycystic Kidney Disease

Cited by 326 publications

References 32 publications

Genomic Organization and Functional Analysis of Murine PKD2L1

Genomic Organization and Functional Analysis of Murine PKD2L1

Genotype-Renal Function Correlation in Type 2 Autosomal Dominant Polycystic Kidney Disease

Progressive Loss of Renal Function Is an Age-Dependent Heritable Trait in Type 1 Autosomal Dominant Polycystic Kidney Disease

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