title: Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease.
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 < or = 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 to 78.1] versus 68.1 [95% CI, 66.0 to 70.2] yr) and CRF (72.5 [95% CI, 70.1 to 74.9] versus 63.7 [95% CI, 61.4 to 66.0] yr). 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 < 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.
authors.affiliation: Division of Nephrology and Genomic Medicine, University Health Network, 200 Elizabeth Street, Toronto, Canada M5G 2C4.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Magistroni
authors.forename: Ning
authors.initials: N
authors.lastname: He
authors.forename: Kairong
authors.initials: K
authors.lastname: Wang
authors.forename: Robin
authors.initials: R
authors.lastname: Andrew
authors.forename: Ann
authors.initials: A
authors.lastname: Johnson
authors.forename: Patricia
authors.initials: P
authors.lastname: Gabow
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dicks
authors.forename: Patrick
authors.initials: P
authors.lastname: Parfrey
authors.forename: Roser
authors.initials: R
authors.lastname: Torra
authors.forename: Jose L
authors.initials: JL
authors.lastname: San-Millan
authors.forename: Eliecer
authors.initials: E
authors.lastname: Coto
authors.forename: Marjan
authors.initials: M
authors.lastname: Van Dijk
authors.forename: Martijn
authors.initials: M
authors.lastname: Breuning
authors.forename: Dorien
authors.initials: D
authors.lastname: Peters
authors.forename: Nadja
authors.initials: N
authors.lastname: Bogdanova
authors.forename: Giulia
authors.initials: G
authors.lastname: Ligabue
authors.forename: Alberto
authors.initials: A
authors.lastname: Albertazzi
authors.forename: Nick
authors.initials: N
authors.lastname: Hateboer
authors.forename: Kyproula
authors.initials: K
authors.lastname: Demetriou
authors.forename: Alkis
authors.initials: A
authors.lastname: Pierides
authors.forename: Constantinos
authors.initials: C
authors.lastname: Deltas
authors.forename: Peter
authors.initials: P
authors.lastname: St  George-Hyslop
authors.forename: David
authors.initials: D
authors.lastname: Ravine
authors.forename: York
authors.initials: Y
authors.lastname: Pei
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D018389:Codon, Nonsense; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D007668:Kidney / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D016366:Open Reading Frames / Q000235:genetics; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D012720:Severity of Illness Index; D017678:Sex Distribution; D050396:TRPP Cation Channels
chemical_list: D018389:Codon, Nonsense; D008565:Membrane Proteins; D011506:Proteins; D022821:RNA Splice Sites; D050396:TRPP Cation Channels