Polycystin-1 expression in PKD1, early-onset PKD1, and TSC2/PKD1 cystic tissue

Albert C.M. Ong, Peter C. Harris, David R. Davies, Lynn Pritchard, Sandro Rossetti, Simon Biddolph, David J.T. Vaux, Nicola Migone, Christopher J. Ward

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

Background. The mutational mechanism responsible for cyst formation in polycystic kidney disease 1 gene (PKD1) remains controversial, with data indicating a two-hit mechanism, but also evidence of polycystin-1 expression in cystic tissue. Methods. To investigate this apparent paradox, we analyzed polycystin-1 expression in cystic renal or liver tissue from 10 patients with truncating PKD1 mutations (including one early-onset case) and 2 patients with severe disease associated with contiguous deletions of TSC2 and PKD1, using monoclonal antibodies (mAbs) to both extreme N-(7e12) and C-terminal (PKS-A) regions of the protein. Truncation of the C-terminal epitope from the putative mutant proteins in each case allowed exclusive assessment of the nontruncated protein with PKS-A. Results. In adult PKD1 tissue, the majority of cysts (approximately 80%) showed polycystin-1 expression, although staining was absent in a variable but significant minority (approximately 20%), in spite of the normal expression of marker proteins. Unlike adult PKD1, however, negative cysts were rarely found in infantile PKD1 or TSC2/PKD1 deletion cases. Conclusions. If a two-hit mutational mechanism is operational, these results suggest that the majority of somatic mutations in adult PKD1 are likely to be missense changes. The low level of polycystin-1- negative cysts in the three 'early-onset' cases, however, suggests that a somatic PKD1 mutation may not always be required for cyst formation.

Original languageEnglish (US)
Pages (from-to)1324-1333
Number of pages10
JournalKidney international
Volume56
Issue number4
DOIs
StatePublished - 1999

Keywords

  • ADPKD
  • Cystogenesis
  • Gene mutations
  • Polycystic kidney disease
  • TSC2

ASJC Scopus subject areas

  • Nephrology

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