Bilineal Disease and Trans-Heterozygotes in Autosomal Dominant Polycystic Kidney Disease

Pei, York; Paterson, Andrew D.; Wang, Kai Rong; He, Ning; Hefferton, Donna; Watnick, Terry; Germino, Gregory G.; Parfrey, Patrick S.; Somlo, Stefan; George-Hyslop, Peter St

doi:10.1086/318188

Cited by 143 publications

(100 citation statements)

References 41 publications

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“…Specifically, the risk of disease in the offspring of an affected spousal pair is increased from 50% to 75%, with one in four children expected to be more severely affected from carrying two mutant alleles. 21 Although bilineal disease may be obvious from the family history, this was not the case in TOR87. When a family history of ADPKD is apparent, the spouse of an affected subject, who may be affected with a mild form of the disease, is rarely screened.…”

Section: Discussionmentioning

confidence: 95%

Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease

Hwang

Conklin

Chan

et al. 2015

JASN

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133

143

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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] [

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Section: Discussionmentioning

confidence: 95%

Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease

Hwang

Conklin

Chan

et al. 2015

JASN

Self Cite

133

143

View full text Add to dashboard Cite

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“…Should this be the case, a threshold model for polycystin 2 within individual epithelial cells of patients with such mutations may provide an additional mechanism for the cystogenic process. Under this model, individual cells with low levels of a functional polycystin may be triggered into a cystogenic pathway by local stresses and other stochastic factors (36,37). Alternatively, it is possible that the above observation may be spurious, given the borderline statistical association and the presence of a significant "modifier effect" (see below).…”

Section: Discussionmentioning

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

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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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“…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).…”

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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

191

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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Bilineal Disease and Trans-Heterozygotes in Autosomal Dominant Polycystic Kidney Disease

Cited by 143 publications

References 41 publications

Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease

Refining Genotype-Phenotype Correlation in 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

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