TY - JOUR
T1 - Somatic PKD2 mutations in individual kidney and liver cysts support a 'two-hit' model of cystogenesis in type 2 autosomal dominant polycystic kidney disease
AU - Pei, York
AU - Watnick, Terry
AU - He, Ning
AU - Wang, Kairong
AU - Liang, Yan
AU - Parfrey, Patrick
AU - Germino, Gregory
AU - St. George-Hyslop, Peter
N1 - Funding Information:
This study was supported in part by grants from the Kidney Foundation of Canada, the Medical Research Council of Canada, the American Polycystic Kidney Research Foundation, and National Institutes of Health (Grants RO1DK48006 and K08DK02562). We thank the study patients and their families for participation, and Drs. Ester Szaky and John Doucet for their help in the tissue retrieval.
PY - 1999/7
Y1 - 1999/7
N2 - 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.
AB - 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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M3 - Article
C2 - 10405208
AN - SCOPUS:0033033706
SN - 1046-6673
VL - 10
SP - 1524
EP - 1529
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 7
ER -