Knockdown of the BBS10 Gene Product Affects Apical Targeting of AQP2 in Renal Cells: A Possible Explanation for the Polyuria Associated with Bardet-Biedl Syndrome

Objective: Bardet-Biedl syndrome (BBS) is a rare genetic disorder whose clinical features include renal abnormalities, which ranges from renal malformations to renal failure. Polyuria and iso-hyposthenuria are common renal dysfunctions in BBS patients even in the presence of normal GFR. The mechanism underlying this defect is unknown and no genotype-phenotype correlation has yet been reported. Here we report four BBS patients showing different renal phenotypes: one had polyuria with hyposthenuria associated with mutation of BBS10, while three patients with normal urine concentrating ability had mutations in BBS1. Methods: We measured aquaporin 2 (AQP2) urinary excretions in BBS patients and studied the possible role of BBS1 and BBS10 on AQP2 trafficking in a mouse cortical collecting duct cell line. Results: We found that the BBS1-mutated patients showed a significant increase of water channel AQP2 urine excretion in antidiuresis. In contrast, the BBS10-mutated patient showed no difference in AQP2 excretion in antidiuresis and after an acute water load. In mouse kidney cortical collecting duct MCD4 cells, knockdown of BBS10, but not of BBS1, prevented the forskolin-dependent trafficking of AQP2 to the apical membrane, and induced the mis-trafficking to the basolateral membrane. Interestingly, BBS10 knockdown was associated with a dramatic reduction of tubulin acetylation without loss of cell polarity. Conclusions: Therefore, the effect of BBS10 knockdown in vitro is consistent with the hyposthenuria observed in the patient with mutation of BBS10. This correlation between renal phenotype and genotype indicates that BBS10, but not BBS1, might control the trafficking of AQP2 and therefore plays a key role in the renal concentrating mechanism.