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Review
. 2020 Jun 29;5(9):1403-1415.
doi: 10.1016/j.ekir.2020.06.017. eCollection 2020 Sep.

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

Emanuela Marchese  1   2 , Margherita Ruoppolo  2   3   4 , Alessandra Perna  5 , Giovambattista Capasso  5   6 , Miriam Zacchia  5
Affiliations
Review

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

Emanuela Marchese et al. Kidney Int Rep. .

Abstract

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. This study is a comprehensive analysis of the literature aiming to collect available information providing mechanistic insights into the pathogenesis of kidney disease by analyzing clinical and basic science studies focused on this issue. The analysis revealed that the syndrome is either clinically and genetically heterogenous, with 24 genes discovered to date, but with 3 genes (BBS1, BBS2, and BBS10) accounting for almost 50% of diagnoses; genotype-phenotype correlation studies showed that patients with BBS1 mutations have a less severe renal phenotype than the other 2 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, like the retina; surprisingly, Bbs1 is the only locus with basal overexpression in the kidney. In vitro studies indicate that signalling pathways involved in embryonic kidney development and 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 shows an age-dependent progression. Data on the exact contribution of local versus systemic consequences of Bbs dysfunction are scanty and further investigations are required to get firm conclusions.

Keywords: Bardet–Biedl syndrome; ciliopathies; genetics; kidney disease; physiopathology.

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Figures

Figure 1
Figure 1
Putative abnormal signalling pathways contributing to the pathogenesis of kidney disease in Bardet-Biedl syndrome (BBS). (a) Sonic hedgehog (Shh) signalling: upon binding of Hh to Patched1 (Ptch1), Smoothened (Smo) is released from Ptch1 and accumulates in the primary cilia (PC). In the PC, Smo induces translocation of Gli activated (GliA) proteins to the tip of the PC by intraflagellar transport. The BBSome, via BBS3/arl6, regulates ciliary trafficking of Gli proteins. GliAs translocate to the nucleus and regulates the transcription of several Shh target genes. Notch signalling: Notch receptor undergoes endosomal sorting for either degradation or recycling to the plasma membrane. Plasma membrane recycling requires BBS1 and BBS4. After binding its ligand, Notch receptor undergoes clivation and the Notch intracellular domain (NICD) translocates to the nucleus and regulates the transcription of downstream targets. Mammalian target of rapamycin (mTOR) signalling: CCDC28B interacts with several BBSome components. It is a positive regulator of mTorc2 activity by binding directly SN1 and affecting mTorc2 assembly/stability. Rapamycin treatment inhibited mTOR signalling and rescued renal cystic phenotype in a BBS zebrafish model. (b) Wnt signalling: several Wnt signalling components localize to the basal body of the kidney PC, including inversin, dishevelled, and Fat4. Knockdown of several BBS results in overactivation of WNT signaling.
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