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

Background. The mutational mechanism responsible for cyst formation in poly cystic kidney disease 1 gene (PKD1) remains controversial, with data indica ting a two-hit mechanism, but also evidence of polycystin-1 expression in c ystic tissue. Methods. To investigate this apparent paradox, we analyzed polycystin-1 exp ression in cystic renal or liver tissue from 10 patients with truncating PK D1 mutations (including one early-onset cage) and 2 patients with severe di sease associated with contiguous deletions of TSC2 and PKD1, using monoclon al antibodies (mAbs) to both extreme N-(7e12) and C-terminal (PKS-A) region s of the protein. Truncation of the C-terminal epitope from the putative mu tant 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%) sh owed polycystin-1 expression, although staining was absent in a variable bu t significant minority (approximately 20%), in spite of the normal expressi on of marker proteins. Unlike adult PKD1, however, negative cysts were rare ly found in infantile PKD1 or TSC2/PKD1 deletion cases. Conclusions. If a two-hit mutational mechanism is operational, these result s suggest that the majority of somatic mutations in adult PKD1 are likely t o be missense changes. The low level of polycystin-1-negative cysts in the three "early-onset" cases, however, suggests that a somatic PKD1 mutation m ay not always be required for cyst formation.