Exploring Key Challenges of Understanding the Pathogenesis of Kidney Disease in Bardet-Biedl Syndrome.

Bardet-Biedl syndrome (BBS) is a rare pleiotropic inherited disorder, known as a ciliopathy. Kidney disease is a cardinal clinical feature; however, it is one of the less investigated traits. The present study is a comprehensive analysis of the literature aiming to collect available information providing mechanistic insights into the pathogenesis of kidney disease, by analysing clinical and basic science studies focused on this issue. The analyses revealed that the syndrome is either clinically and genetically heterogenous, with 24 genes discovered to date, but with three of them, namely BBS1,BBS2 and BBS10, accounting for almost 50% of diagnosis; genotype-phenotype correlation studies demonstrated that BBS1-mutated patients showed a less severe renal phenotype than the other two most common loci; in addition, truncating rather than missense mutations are more likely to cause kidney disease. However, significant intrafamilial clinical variability has been described, with no clear explanation to date. In mice kidneys, Bbs genes have relative low expression levels, in contrast with other common affected organs, as the retina; surprisingly, Bbs1 is over-expressed in the kidney. In vitro studies indicate that signalling pathways involved in embryonic kidney development and kidney repair are affected in the context of BBS depletion; in mice, kidney disease does not have a full penetrance; when present, it resembles human phenotype and progresses over time. Data on the exact contribution of local vs systemic consequences of Bbs dysfunction are scanty and further investigations are required to get firm conclusions.