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A Loss-of-Function Model for Cystogenesis in Human Autosomal Dominant Polycystic Kidney Disease Type 2

Authors
  • Torra, Roser
  • Badenas, Cèlia
  • San Millán, José L.
  • Pérez-Oller, Laureano
  • Estivill, Xavier
  • Darnell, Alejandro
Type
Published Article
Journal
The American Journal of Human Genetics
Publisher
Elsevier BV
Publication Date
Jan 01, 1999
Accepted Date
May 20, 1999
Volume
65
Issue
2
Pages
345–352
Identifiers
DOI: 10.1086/302501
Source
Elsevier
Keywords
License
Unknown

Abstract

Summary Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous, with at least three chromosomal loci ( PKD1, PKD2, and PKD3) that account for the disease. Mutations in the PKD2 gene, on the long arm of chromosome 4, are expected to be responsible for ∼15% of cases of ADPKD. Although ADPKD is a systemic disease, it shows a focal expression, because <1% of nephrons become cystic. A feasible explanation for the focal nature of events in PKD1, proposed on the basis of the two-hit theory, suggests that cystogenesis results from the inactivation of the normal copy of the PKD1 gene by a second somatic mutation. The aim of this study is to demonstrate that somatic mutations are present in renal cysts from a PKD2 kidney. We have studied 30 renal cysts from a patient with PKD2 in which the germline mutation was shown to be a deletion that encompassed most of the disease gene. Loss-of-heterozygosity (LOH) studies showed loss of the wild-type allele in 10% of cysts. Screening of six exons of the gene by SSCP detected eight different somatic mutations, all of them expected to produce truncated proteins. Overall, ⩾37% of the cysts studied presented somatic mutations. No LOH for the PKD1 gene or locus D3S1478 were observed in those cysts, which demonstrates that somatic alterations are specific. We have identified second-hit mutations in human PKD2 cysts, which suggests that this mechanism could be a crucial event in the development of cystogenesis in human ADPKD-type 2.

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