Genetic Heterogeneity of Polycystic Kidney Disease in Europe1

Peters, Dorien J.M.; Sandkuijl, L. A.

doi:10.1159/000421651

Cited by 260 publications

(129 citation statements)

References 0 publications

Supporting

Mentioning

123

Contrasting

Order By: Relevance

“…2,3 Previous studies of European families ascertained through probands enriched with renal failure reported that approximately 85% and approximately 15% of ADPKD families were linked to the PKD1 and PKD2 loci, respectively. 3 However, a higher prevalence of PKD2 of 26% has been recently reported in a population-based study. 4 Disease progression of ADPKD is highly variable, in part because of a strong gene locus effect.…”

mentioning

confidence: 92%

Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease

Hwang

Conklin

Chan

et al. 2015

JASN

133

143

View full text Add to dashboard Cite

Renal disease variability in autosomal dominant polycystic kidney disease (ADPKD) is strongly influenced by the gene locus (PKD1 versus PKD2). Recent studies identified nontruncating PKD1 mutations in approximately 30% of patients who underwent comprehensive mutation screening, but the clinical significance of these mutations is not well defined. We examined the genotype-renal function correlation in a prospective cohort of 220 unrelated ADPKD families ascertained through probands with serum creatinine #1.4 mg/dl at recruitment. We screened these families for PKD1 and PKD2 mutations and reviewed the clinical outcomes of the probands and affected family members. Height-adjusted total kidney volume (htTKV) was obtained in 161 affected subjects. Multivariate Cox proportional hazard modeling for renal and patient survival was performed in 707 affected probands and family members. Overall, we identified pathogenic mutations in 84.5% of our families, in which the prevalence of PKD1 truncating, PKD1 in-frame insertion/deletion, PKD1 nontruncating, and PKD2 mutations was 38.3%, 4.3%, 27.1%, and 30.3%, respectively. Compared with patients with PKD1 truncating mutations, patients with PKD1 in-frame insertion/deletion, PKD1 nontruncating, or PKD2 mutations have smaller htTKV and reduced risks (hazard ratio Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease worldwide, responsible for 5%-10% of ESRD. 1,2 Mutations in two genes (PKD1 and PKD2) account for most patients with ADPKD. 2,3 Previous studies of European families ascertained through probands enriched with renal failure reported that approximately 85% and approximately 15% of ADPKD families were linked to the PKD1 and PKD2 loci, respectively. 3 However, a higher prevalence of PKD2 of 26% has been recently reported in a population-based study. 4 Disease progression of ADPKD is highly variable, in part because of a strong gene locus effect. [5][6][7][8] Adjusted for age, patients with PKD1 have larger kidneys and earlier onset of ESRD than patients with PKD2 (mean age at ESRD, 53.4 versus 72.7 years old, respectively). 5,6,8 Additionally, significant intrafamilial renal disease variability in ADPKD suggests a modifier effect. [9][10][11] [

show abstract

mentioning

confidence: 92%

Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease

Hwang

Conklin

Chan

et al. 2015

JASN

133

143

View full text Add to dashboard Cite

show abstract

“…1 Approximately 85% of cases are because of PKD1 mutations and in 15% the disease is caused by a mutation in PKD2. 2 Both PKD1 and PKD2 are expressed in a variety of cell types and tissues including renal epithelium, hepatic bile ducts, pancreatic ducts, vascular smooth muscle cells (SMCs) and endothelial cells (ECs). [3][4][5] ADPKD is also associated with cysts in the liver and pancreas as well as cardiovascular complications such as hypertension and aneurysms.…”

mentioning

confidence: 99%

Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension

Hassane¹,

Claij²,

Jodar³

et al. 2011

Laboratory Investigation

View full text Add to dashboard Cite

Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder characterized by renal, hepatic and pancreatic cyst formation and cardiovascular complications. The condition is caused by mutations in the PKD1 or PKD2 gene. In mice with reduced expression of Pkd1, dissecting aneurysms with prominent media thickening have been seen. To study the effect of selective disruption of Pkd1 in vascular smooth muscle cells (SMCs), we have generated mice in which a floxed part of the Pkd1 gene was deleted by Cre under the control of the SM22 promotor (SM22-Pkd1 del/del mice). Cre activity was confirmed by X-gal staining using lacZ expressing Cre reporter mice (R26R), and quantitative PCR indicated that in the aorta Pkd1 gene expression was strongly reduced, whereas Pkd2 levels remained unaltered. Histopathological analysis revealed cyst formation in pancreas, liver and kidneys as the result of extravascular Cre activity in pancreatic ducts, bile ducts and in the glomerular Bowman's capsule. Remarkably, we did not find any spontaneous gross structural blood vessel abnormalities in mice with somatic Pkd1 gene disruption in SMCs or simultaneous disruption of Pkd1 in SMCs and endothelial cells (ECs). Extensive isometric myographic analysis of the aorta did not reveal differences in response to KCl, acetylcholine, phenylephrin or serotonin, except for a significant increase in contractility induced by phenylephrin on arteries from 40 weeks old Pkd1 del/ þ germ-line mice. However, SM22-Pkd1 del/del mice showed significantly reduced decrease in heart rate on angiotensin II-induced hypertension. The present findings further demonstrate in vivo, that adaptation to hypertension is altered in SM22-Pkd1 del/del mice.

show abstract

“…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). Mutations of PKD1 and PKD2 account for the disease in approximately 80 to 85% and approximately 10 to 15% of Caucasian ADPKD families, respectively (1,10). Polycystins 1 and 2, the gene products of PKD1 and PKD2, are transmembrane proteins that share sequence homology and are currently thought to be part of a novel signaling pathway that regulates intracellular calcium (11)(12)(13).…”

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

View full text Add to dashboard Cite

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.

show abstract

Genetic Heterogeneity of Polycystic Kidney Disease in Europe1

Cited by 260 publications

References 0 publications

Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease

Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease

Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension

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

Contact Info

Product

Resources

About