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

Riccardo Magistroni^*,, Ning He^*, Kairong Wang^*, Robin Andrew^*, Ann Johnson, Patricia Gabow, Elizabeth Dicks, Patrick Parfrey, Roser Torra, Jose L. San-Millan^¶, Eliecer Coto^#, Marjan van Dijk^@, Martijn Breuning^**, Dorien Peters^**, Nadja Bogdanova, Giulia Ligabue, Alberto Albertazzi, Nick Hateboer, Kyproula Demetriou^¶¶, Alkis Pierides^¶¶, Constantinos Deltas^##, Peter St. George-Hyslop^*, David Ravine and York Pei^*

*Division of Genomic Medicine, University Health Network, Toronto, Canada; Renal Division, University of Colorado Health Sciences Center, Denver, CO; Division of Nephrology, Memorial University, St. John’s, Newfoundland, Canada; Division of Nephrology, Fundacio Puigvert, Barcelona, Spain; ^¶Unidad de Genetica Molecular, Hospital Ramon y Cajal, Madrid, Spain; ^#Instituto Reina Sofia de Investigaciones Nephrologicas, Hospital Central de Asturias, Oviedo, Spain; ^@Academisch Ziekenhuis and **Afdeling Anthropogenetica Rijksuniversiteit Leiden, Leiden, the Netherlands; Institut Fur Humangenetik, Westfalische Wilheims-Universitat, Munster, Germany; Division of Nephrology, University of Modena and Reggio Emilia, Modena, Italy; Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK; ^¶¶Department of Nephrology, Nicosia General Hospital, Cyprus; and ^##Department of Biological Sciences, University of Cyprus and Department of Molecular Genetics, Cyprus Institute of Neurology and Genetics, Cyprus.

Correspondence to Dr. York Pei, Division of Nephrology and Genomic Medicine, University Health Network, 13 EN-228, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. Phone: 416-340-4257; Fax: 416-340-4999;

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 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. E-mail: york.pei@uhn.on.ca

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