Mutations of PKD1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous mutations

Watnick, Terry; He, Ning; Wang, K; Liang, Yan; Parfrey, Patrick S.; Hefferton, Donna; George-Hyslop, Peter St; Germino, Gregory G.; Pei, York

doi:10.1038/75981

Cited by 118 publications

(91 citation statements)

References 14 publications

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“…Most PKD2 mutations are also predicted to truncate the C'-terminus of polycystin 2; it therefore appears that the loss of the coil-coil interaction region with polycystin 1 (i.e., the most distal C'-terminal functional domain so far identified) may be sufficient to completely inactivate the mutant protein (11,12,14). Recent human (31)(32)(33) and knockout mouse (34,35) studies have suggested that a common mechanism for individual cyst formation in ADPKD results from the inactivation of PKD1 or PKD2 within an epithelial cell, through germline and somatic mutations. Our data are consistent with this classical two-hit model of cystogenesis in ADPKD and suggest that most PKD2 mutations are completely inactivating.…”

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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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

Self Cite

126

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“…Recent studies suggested that biallelic PKD1 or PKD2 inactivation from germline and somatic mutations within individual epithelial cells is a major mechanism for focal cyst formation in ADPKD. [21][22][23][24][25] Accordingly, the frequency of somatic PKD mutations is predicted to influence the total cyst number in ADPKD. 25 Because of its large size and complexity, PKD1 is thought to be four to five times more prone to mutations than PKD2, 26 which may account for the difference in renal disease severity between the two gene types.…”

Section: Discussionmentioning

confidence: 99%

Unified Criteria for Ultrasonographic Diagnosis of ADPKD

Pei

Obaji

Dupuis

et al. 2009

Journal of the American Society of Nephrology

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626

448

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Individuals who are at risk for autosomal dominant polycystic kidney disease are often screened by ultrasound using diagnostic criteria derived from individuals with mutations in PKD1. Families with mutations in PKD2 typically have less severe disease, suggesting a potential need for different diagnostic criteria. In this study, 577 and 371 at-risk individuals from 58 PKD1 and 39 PKD2 families, respectively, were assessed by renal ultrasound and molecular genotyping. Using sensitivity data derived from genetically affected individuals and specificity data derived from genetically unaffected individuals, various diagnostic criteria were compared. In addition, data sets were created to simulate the PKD1 and PKD2 case mix expected in practice to evaluate the performance of diagnostic criteria for families of unknown genotype. The diagnostic criteria currently in use performed suboptimally for individuals with mutations in PKD2 as a result of reduced test sensitivity. In families of unknown genotype, the presence of three or more (unilateral or bilateral) renal cysts is sufficient for establishing the diagnosis in individuals aged 15 to 39 y, two or more cysts in each kidney is sufficient for individuals aged 40 to 59 y, and four or more cysts in each kidney is required for individuals Ն60 yr. Conversely, fewer than two renal cysts in at-risk individuals aged Ն40 yr is sufficient to exclude the disease. These unified diagnostic criteria will be useful for testing individuals who are at risk for autosomal dominant polycystic kidney disease in the usual clinical setting in which molecular genotyping is seldom performed.

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“…However, patients with ADPKD are heterozygotes, having inherited one mutant and one normal allele of the PKD1 or PKD2 genes. Studies of cyst-lining epithelial cells isolated from individual cysts in both disorders have demonstrated loss of heterozygosity at the wild-type PKD1 allele 8,9 that has led to a two-hit mechanism for cyst formation. This mechanism requires not only a germ-line mutation of PKD1 or PKD2 but also an additional somatic mutation in the wild-type gene to initiate the formation of cysts.…”

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confidence: 99%

Defining a Link with Autosomal-Dominant Polycystic Kidney Disease in Mice with Congenitally Low Expression of Pkd1

Jiang

Chiou

Wang

et al. 2006

The American Journal of Pathology

114

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Mouse models for autosomal-dominant polycystic kidney disease (ADPKD), derived from homozygous targeted disruption of Pkd1 gene, generally die in utero or perinatally because of systemic defects. We introduced a loxP site and a loxP-flanked mc1-neo cassette into introns 30 and 34, respectively, of the Pkd1 locus to generate a conditional, targeted mutation. Significantly, before excision of the floxed exons and mc1-neo from the targeted locus by Cre recombinase, mice homozygous for the targeted allele appeared normal at birth but developed polycystic kidney disease with a slower progression than that of Pkd-null mice. Further, the homozygotes continued to produce low levels of full-length Pkd1-encoded protein, suggesting that slight Pkd1 expression is sufficient for renal cyst formation in ADPKD. In this viable model, up-regulation of heparin-binding epidermal growth factor-like growth factor accompanied increased epidermal growth factor receptor signaling, which may be involved in abnormal proliferation of the cyst-lining epithelia. Increased apoptosis in cyst epithelia was only observed in the later period that correlated with the cyst regression. Abnormalities in Na ؉ /K ؉ -ATPase, aquaporin-2, and vasopressin V2 receptor expression were also identified. This mouse model may be suitable for further studies of progression and therapeutic interventions of ADPKD.

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Mutations of PKD1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous mutations

Cited by 118 publications

References 14 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

Unified Criteria for Ultrasonographic Diagnosis of ADPKD

Defining a Link with Autosomal-Dominant Polycystic Kidney Disease in Mice with Congenitally Low Expression of Pkd1

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