Figure 915

Autosomal-dominant polycystic kidney disease: predicted structure of polycystin 1 and polycystin 2 and their interaction. Polycystin 1 is a 4302-amino acid protein, which anchors itself to cell membranes by seven transmembrane domains [10]. The large extracellular portion includes two leucine-rich repeats usually involved in protein-protein interactions and a C-type lectin domain capable of binding carbohydrates. A part of the intracellular tail has the capacity to form a coiled-coil motif, enabling either self-assembling or interaction with other proteins. Polycystin 2 is a 968-amino acid protein with six transmembrane domains, resembling a subunit of voltage-activated calcium channel. Like polycystin 1, the C-termi-nal end of polycystin 2 comprises a coiled-coil domain and is able to interact in vitro with PKD2 [11]. This C-terminal part of poly-cystin 2 also includes a calcium-binding domain. On these grounds, it has been hypothesized that polycystin 1 acts like a receptor and signal transducer, communicating information from outside to inside the cell through its interaction with polycystin 2. This coordinated function could be crucial during late renal embryogenesis. It is currently speculated that both polycystins play a role in the maturation of tubule epithelial cells. Mutation of polycystins could thus impair the maturation process, maintaining some tubular cells in a state of underdevelopment. This could result in both sustained cell proliferation and predominance of fluid secretion over absorption, leading to cyst formation (see Fig. 9-16 and references 12 and 13 for review). (From Hughes et al. [10] and Germino [12].)

Thickened tubular basement membrane

Thickened tubular basement membrane

Normal tubule with germinal i PKD1 mutation in each cell

Occurrence N of somatic ■ mutation of the normal PKD1 allele in one tubular cell (the "second hit")

Monoclonal » proliferation i leading to cyst formation

Isolated cyst disconnected from its tubule of origin

Normal tubule with germinal i PKD1 mutation in each cell

Occurrence N of somatic ■ mutation of the normal PKD1 allele in one tubular cell (the "second hit")

Monoclonal » proliferation i leading to cyst formation

Isolated cyst disconnected from its tubule of origin

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