Molecular Medicine, Genetics and DevelopmentSomaticPKD2Mutations in Individual Kidney and Liver Cysts Support a “Two-Hit” Model of Cystogenesis in Type 2 Autosomal Dominant Polycystic Kidney DiseasePEI, YORK*; WATNICK, TERRY†; HE, NING*; WANG, KAIRONG*; LIANG, YAN‡; PARFREY, PATRICK§; GERMINO, GREGORY†; ST. GEORGE-HYSLOP, PETER*,‡ Author Information *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: [email protected] Received March 2, 1999. Accepted April 9, 1999. Journal of the American Society of Nephrology 10(7):p 1524-1529, July 1999. | DOI: 10.1681/ASN.V1071524 Buy Metrics 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. Copyright © 1999 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.