Location of mutations within the PKD2 gene influences clinical outcome

Hateboer, Nick; Veldhuisen, Barbera; Peters, Dorien J.M.; Breuning, Martijn H.; San-Millán, José L.; Bogdanova, Nadja; Coto, Eliécer; Dijk, Marjan A. van; Afzal, Ali R.; Jeffery, Steve; Saggar-Malik, A. K.; Torra, Roser; Dimitrakov, D; Martı́nez, Iciar; Castro, Saturnino Sanz de; Krawczak, Michael; Ravine, David

doi:10.1046/j.1523-1755.2000.00989.x

Cited by 67 publications

(42 citation statements)

References 37 publications

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“…This is consistent with the finding of significant renal disease variability within families with PKD1-linkage (38) and among patients with the same PKD1 mutations (16). Taken together, these data suggest the existence of a modifier effect for AD-PKD (17,38,39). Recent studies have shown that the phenotypic variability of a number of Mendelian disorders is in fact complex because of the existence and interaction of genetic and environmental modifiers (40).…”

Section: Discussionsupporting

confidence: 88%

“…However, considerable renal disease variability (age range of onset of ESRD, 40 to 88 yr) was also evident between individual patients. described (17)(18)(19)(20)(21)(22)(23)(24)(25), and the remaining mutations from 21 families are reported here for the first time. The diagnosis of ADPKD in the patients and at-risk individuals from each study family was established using well-established ultrasound-based criteria (26).…”

Section: Study Patientsmentioning

confidence: 96%

“…DNA isolation and mutation screening methods have been previously detailed (17)(18)(19)(20)(21)(22)(23)(24). Single-stranded conformational polymorphism (SSCP), heteroduplex analysis (HA), or direct sequencing was employed to screen all 15 exons and their flanking intronic sequences of PKD2 (28) for PKD2 mutations in one definitively affected individual from each study family.…”

Section: Pkd2 Mutational Analysesmentioning

confidence: 99%

“…In the first study, patients with mutations in the 3' half of PKD1 had milder renal disease than patients with mutations in the 5' half of the gene (16). In the second study, patients with mutations in the 3' half of PKD2 had milder composite scores for renal complications (i.e., presence or absence of hypertension, hematuria, renal calculi, and urinary tract infection) than patients with mutations in the 5' half of the gene (17). However, correlation of renal function with genotype data has not been assessed in the patients with PKD2 mutations.…”

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confidence: 95%

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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

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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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Section: Discussionsupporting

confidence: 88%

Section: Study Patientsmentioning

confidence: 96%

Section: Pkd2 Mutational Analysesmentioning

confidence: 99%

mentioning

confidence: 95%

See 2 more Smart Citations

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

Self Cite

126

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“…Significant interfamilial phenotypic differences have been described, and clinically mild PKD1 families documented (22)(23)(24). Furthermore, it has been suggested that the location of the PKD2 mutation influences the clinical outcome (25). An anecdotal association of a specific mutation in three families with early onset disease and/or associated vascular complications has also been reported (26).…”

mentioning

confidence: 99%

The Position of the Polycystic Kidney Disease 1 (PKD1) Gene Mutation Correlates with the Severity of Renal Disease

Rossetti

Burton

Strmecki

et al. 2002

Journal of the American Society of Nephrology

190

136

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Abstract. The severity of renal cystic disease in the major form of autosomal dominant polycystic kidney disease (PKD1) is highly variable. Clinical data was analyzed from 324 mutation-characterized PKD1 patients (80 families) to document factors associated with the renal outcome. The mean age to end-stage renal disease (ESRD) was 54 yr, with no significant difference between men and women and no association with the angiotensin-converting enzyme polymorphism. Considerable intrafamilial variability was observed, reflecting the influences of genetic modifiers and environmental factors. However, significant differences in outcome were also found among families, with rare examples of unusually late-onset PKD1. Possible phenotype/genotype correlations were evaluated by estimating the effects of covariants on the time to ESRD using proportional hazards models. In the total population, the location of the mutation (in relation to the median position; nucleotide 7812), but not the type, was associated with the age at onset of ESRD. Patients with mutations in the 5' region had significantly more severe disease than the 3' group; median time to ESRD was 53 and 56 yr, respectively (P ϭ 0.025), with less than half the chance of adequate renal function at 60 yr (18.9% and 39.7%, respectively). This study has shown that the position of the PKD1 mutation is significantly associated with earlier ESRD and questions whether PKD1 mutations simply inactivate all products of the gene.

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Congenital and Structural Abnormalities of the Liver

and¹,

Schwarz²

2003

Diseases of the Liver and Biliary System in Children

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Location of mutations within the PKD2 gene influences clinical outcome

Cited by 67 publications

References 37 publications

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

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

The Position of the Polycystic Kidney Disease 1 (PKD1) Gene Mutation Correlates with the Severity of Renal Disease

Congenital and Structural Abnormalities of the Liver

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