Comparing the Bbs10 complete knockout phenotype with a specific renal epithelial knockout one highlights the link between renal defects and systemic inactivation in mice

Cognard, Noëlle; Scerbo, M. Julia; Obringer, Cathy; Yu, Xiangxiang; Costa, Fanny; Haser, Elodie; Le, Dane; Stoetzel, Corinne; Roux, Michel J.; Moulin, Anne‐Marie; Dollfus, Hélène; Marion, Vincent

doi:10.1186/s13630-015-0019-8

Cited by 29 publications

(50 citation statements)

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“…Analysis of the phenotype‐genotype links in other symptoms than renal anomalies was less conclusive, with the exception that patients with BBS1 mutations had generally milder disease manifestation than patients with BBS2 mutations. Our analysis documents that previously suggested functional redundancy between BBS4 and BBS5 described in human cell lines, C. elegans and zebrafish (Xu et al, ) and the most severe phenotype of Bbs4 ‐deficient mouse among the available BBS mouse models (Berbari et al, ; Cognard et al, ; Davis et al, ; Guo et al, ; Kulaga et al, ; Loktev & Jackson, ; Nishimura et al, ; Rahmouni et al, ; Tadenev et al, ; Zhang et al, ) do not apply in humans.…”

Section: Discussionsupporting

confidence: 90%

“…Patients with mutations in any of the BBSome‐encoding genes might develop any BBS symptoms. Accordingly, the reported phenotypes of mice deficient in the BBSome‐encoding subunits recapitulate several aspects of the human disease (Berbari et al, ; Cognard et al, ; Kulaga et al, ; Loktev & Jackson, ; Nishimura et al, ; Rahmouni et al, ; Tadenev et al, ; Zhang et al, ). This evidence suggests that all the BBSome subunits are essential for the function of the whole complex and have no independent roles.…”

Section: Introductionmentioning

confidence: 97%

“…Structural similarities between some BBSome subunits (Jin et al, 2010), reported functional redundancies between BBS4 and BBS5 subunits (Xu et al, 2015), multiple differences between particular BBSome-deficient cellular or mouse models (Berbari et al, 2008;Cognard et al, 2015;Guo et al, 2011;Kulaga et al, 2004;Loktev & Jackson, 2013;Nishimura et al, 2004;Rahmouni et al, 2008;Su et al, 2014;Tadenev et al, 2011;Xu et al, 2015;Zhang et al, 2011;Zhang et al, 2013), and partially differential effects of knockdowns of particular BBSome-encoding genes in mouse embryonic brain development (Guo et al, 2015) suggest that particular BBSome subunits might have unique functions. Moreover, it is possible that the BBSome maintains a residual function even in the absence of particular subunits.…”

Section: Introductionmentioning

confidence: 99%

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Meta‐analysis of genotype‐phenotype associations in Bardet‐Biedl syndrome uncovers differences among causative genes

et al. 2019

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Bardet‐Biedl syndrome (BBS) is a recessive genetic disease causing multiple organ anomalies. Most patients carry mutations in genes encoding for the subunits of the BBSome, an octameric ciliary transport complex, or accessory proteins involved in the BBSome assembly or function. BBS proteins have been extensively studied using in vitro, cellular, and animal models. However, the molecular functions of particular BBS proteins and the etiology of the BBS symptoms are still largely elusive. In this study, we applied a meta‐analysis approach to study the genotype‐phenotype association in humans using our database of all reported BBS patients. The analysis revealed that the identity of the causative gene and the character of the mutation partially predict the clinical outcome of the disease. Besides their potential use for clinical prognosis, our analysis revealed functional differences of particular BBS genes in humans. Core BBSome subunits BBS2, BBS7, and BBS9 manifest as more critical for the function and development of kidneys than peripheral subunits BBS1, BBS4, and BBS8/TTC8, suggesting that incomplete BBSome retains residual function at least in the kidney.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Meta‐analysis of genotype‐phenotype associations in Bardet‐Biedl syndrome uncovers differences among causative genes

et al. 2019

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“…Moreover, in Cognard et al ., the authors compared kidney function and structure in total Bbs10 -/- versus a renal epithelial specific Bbs10 knockout mice, to dissect the effect of intrinsic versus systemic BBS inactivation. Total Bbs10 -/- mice recapitulated most of the clinical features of human BBS phenotype, including retinal degeneration, obesity, histological and functional renal impairment whereas the renal epithelial specific Bbs10 knockout mice did not exhibit any structural or functional renal abnormality, suggesting that systemic deletion of BBS10 is required to generate kidney dysfunction in mice [60]. …”

Section: Evidence Supporting the Role Of Systemic Factors In Kidney Dmentioning

confidence: 99%

Impact of Local and Systemic Factors on Kidney Dysfunction in Bardet-Biedl Syndrome

Zacchia

Capolongo

Trepiccione

et al. 2017

Kidney Blood Press Res

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Bardet Biedl syndrome (BBS) is a rare inherited syndromic condition characterized by renal and extra-renal disorders. Renal defect, at either structural or functional level, is one of the cardinal clinical features, and is a major cause of morbidity. However, the pathogenic mechanism underlying its dysfunction remains largely unknown, and to date only symptomatic treatment with no specific therapy is available for these patients. Elucidating aberrant cellular and/or systemic processes that impact kidney function is therefore a prerequisite to develop targeted innovative therapeutic strategies for the BBS patients. Given the proven role of BBS proteins in the function of the primary cilium (PC) and considering the clinical overlapping of BBS with other ciliopathies, BBS is considered the result of disruption of ciliary activities. The present review aims at giving an updated overview of the spectrum of renal abnormalities in BBS patients according to the existing scientific literature, and discusses the possible role of intrinsic PC dysfunction into the pathogenesis of renal defects based on the most recent findings demonstrating a possible role of systemic factors in favoring the progression of renal disease.

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“…Several studies have linked the disruption of cilia homeostasis with defects in renal development and cysts formation, thus BBS is considered the result of ciliary dysfunction and is included in the group of diseases named ciliopathies . Mouse models of BBS have shown that BBS2, BBS4 and BBS10 depletion lead to systemic-related renal disease [15, 16]. In addition, in vitro studies have shown that BBS10 is implicated in the mechanisms mediating water re-absorption along the collecting duct (CD) [17, 18].…”

Section: Introductionmentioning

confidence: 99%

Urine Proteomics Revealed a Significant Correlation Between Urine-Fibronectin Abundance and Estimated-GFR Decline in Patients with Bardet-Biedl Syndrome

Caterino

Zacchia

Costanzo

et al. 2018

Kidney Blood Press Res

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Background:/Aims: Renal disease is a common cause of morbidity in patients with Bardet-Biedl syndrome (BBS), however the severity of kidney dysfunction is highly variable. To date, there is little information on the pathogenesis, the risk and predictor factors for poor renal outcome in this setting. The present study aims to analyze the spectrum of urinary proteins in BBS patients, in order to potentially identify 1) disease-specific proteomic profiles that may differentiate the patients from normal subjects; 2) urinary markers of renal dysfunction. Methods: Fourteen individuals (7 males and 7 females) with a clinical diagnosis of BBS have been selected in this study. A pool of 10 aged-matched males and 10 aged-matched females have been used as controls for proteomic analysis. The glomerular filtration rate (eGFR) has been estimated using the CKD-EPI formula. Variability of eGFR has been retrospectively assessed calculating average annual eGFR decline (ΔeGFR) in a mean follow-up period of 4 years (3-7). Results: 42 proteins were significantly over- or under-represented in BBS patients compared with controls; the majority of these proteins are involved in fibrosis, cell adhesion and extracellular matrix organization. Statistic studies revealed a significant correlation between urine fibronectin (u-FN) (r²=0.28; p<0.05), CD44 antigen (r² =0.35; p<0.03) and lysosomal alfa glucosidase ( r²0.27; p<0.05) abundance with the eGFR. In addition, u-FN (r² =0.2389; p<0.05) was significantly correlated with ΔeGFR. Conclusion: The present study demonstrates that urine proteome of BBS patients differs from that of normal subjects; in addition, kidney dysfunction correlated with urine abundance of known markers of renal fibrosis.

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Comparing the Bbs10 complete knockout phenotype with a specific renal epithelial knockout one highlights the link between renal defects and systemic inactivation in mice

Cited by 29 publications

References 35 publications

Meta‐analysis of genotype‐phenotype associations in Bardet‐Biedl syndrome uncovers differences among causative genes

Meta‐analysis of genotype‐phenotype associations in Bardet‐Biedl syndrome uncovers differences among causative genes

Impact of Local and Systemic Factors on Kidney Dysfunction in Bardet-Biedl Syndrome

Urine Proteomics Revealed a Significant Correlation Between Urine-Fibronectin Abundance and Estimated-GFR Decline in Patients with Bardet-Biedl Syndrome

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