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Somatic PKD2 Mutations in Individual Kidney and Liver Cysts Support a "Two-Hit" Model of Cystogenesis in Type 2 Autosomal Dominant Polycystic Kidney Disease

YORK PEI^*, TERRY WATNICK, NING HE^*, KAIRONG WANG^*, YAN LIANG, PATRICK PARFREY^§, GREGORY GERMINO and PETER ST. GEORGE-HYSLOP^*,

^* Department of Medicine, Toronto Hospital and University of Toronto, Toronto, Ontario, Canada
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada
^§ Division of Nephrology, Department of Medicine, Health Sciences Center, St. Johns, Newfoundland, Canada

Correspondence to Dr. York Pei, Toronto Hospital, 13 EN-228, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. Phone: 416-340-4257; Fax: 416-340-0029; E-mail: ypei{at}torhosp.toronto.on.ca

Abstract. An intriguing feature of autosomal dominant polycystic kidney disease (ADPKD) is the focal and sporadic formation of renal and extrarenal cysts. Recent documentation of somatic PKD1 mutations in cystic epithelia of patients with germ-line PKD1 mutations suggests a "two-hit" model for cystogenesis in type 1 ADPKD. This study tests whether the same mechanism for cystogenesis might also occur in type 2 ADPKD. Genomic DNA was obtained from 54 kidney and liver cysts from three patients with known germ-line PKD2 mutations, using procedures that minimize contamination of cells from noncystic tissue. Using intragenic and microsatellite markers, these cyst samples were screened for loss of heterozygosity. The same samples were also screened for somatic mutations in five of the 15 exons in PKD2 by single-stranded conformational polymorphism analysis. Loss of heterozygosity was found in five cysts, and unique intragenic mutations were found in seven other cysts. In 11 of these 12 cysts, it was also determined that the somatic mutation occurred nonrandomly in the copy of PKD2 inherited from the unaffected parent. These findings support the "two-hit" model as a unified mechanism for cystogenesis in ADPKD. In this model, the requirement of a somatic mutation as the rate-limiting step for individual cyst formation has potential therapeutic implications.

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