Abstract
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 urineconcentrating 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.
Highlights
Bardet-Biedl syndrome (BBS, OMIM #209900) is an autosomal recessive disorder characterized by retinal dystrophy, obesity, hypogenitalism, polydactyly and renal dysfunction [1,2,3,4,5]
We found that the BBS1-mutated patients showed a significant increase of water channel aquaporin 2 (AQP2) urine excretion in antidiuresis
The BBS10-mutated patient showed no difference in AQP2 excretion in antidiuresis and after an acute water load
Summary
Bardet-Biedl syndrome (BBS, OMIM #209900) is an autosomal recessive disorder characterized by retinal dystrophy, obesity, hypogenitalism, polydactyly and renal dysfunction [1,2,3,4,5]. Eighteen genes have been associated with BBS, up to now [7,8,9,10,11]. The various BBS-associated genes encode proteins localized to the primary cilia, basal body, or centrosome, and are involved in the regulation of ciliary structure, biogenesis and function [11]. Proteins BBS1, BBS2, BBS4, BBS5, BBS7, BBS8 and BBS9 form the BBSome complex, which controls the intraflagellar trafficking, while BBS6, BBS10 and BBS12 form the chaperonin complex [11,12]. About 23% and 20% of BBS patients had pathogenic mutations in the BBS1 and BBS10 gene, respectively [6]
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