Bardet-Biedl syndrome proteins regulate intracellular signaling and neuronal function in patient-specific iPSC-derived neurons

Wang, Liheng; Liu, Yang; Stratigopoulos, George; Panigrahi, Sunil K.; Sui, Lina; Zhang, Yiying; LeDuc, Charles A.; Glover, Hannah J; Rosa, Maria Caterina De; Burnett, Lisa C.; Williams, Damian J.; Shang, Linshan; Goland, Robin; Tsang, Stephen H.; Wardlaw, Sharon L.; Egli, Dieter; Zheng, Deyou; Doege, Claudia A.; Leibel, Rudolph L.

doi:10.1172/jci146287

Cited by 36 publications

(31 citation statements)

References 68 publications

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“…We have used immunofluorescence analysis of cilia transport machinery and cargo as readouts of functionality, yet alternative readouts for the effect of TRIDs are possible. Changes to intracellular Ca 2+ , cAMP and insulin levels have been associated with ciliary dysfunction in in vitro BBS models while increased oxidative stress and loss of inflammatory cytokine action have been previously associated with impaired ciliation [67] , [68] , [69] , [70] . Initially, these defects will need to be characterised in ciliopathy models but may act as alternative outcome measures for future studies treating ciliopathies with TRIDs.…”

Section: Discussionmentioning

confidence: 99%

Translational readthrough of ciliopathy genes BBS2 and ALMS1 restores protein, ciliogenesis and function in patient fibroblasts

Eintracht¹,

Forsythe

May-Simera³

et al. 2021

EBioMedicine

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Background Ciliary dysfunction underlies a range of genetic disorders collectively termed ciliopathies, for which there are no treatments available. Bardet-Biedl syndrome (BBS) is characterised by multisystemic involvement, including rod-cone dystrophy and renal abnormalities. Together with Alström syndrome (AS), they are known as the ‘obesity ciliopathies’ due to their common phenotype. Nonsense mutations are responsible for approximately 11% and 40% of BBS and AS cases, respectively. Translational readthrough inducing drugs (TRIDs) can restore full-length protein bypassing in-frame premature termination codons, and are a potential therapeutic approach for nonsense-mediated ciliopathies. Methods Patient fibroblasts harbouring nonsense mutations from two different ciliopathies (Bardet-Biedl Syndrome and Alström Syndrome) were treated with PTC124 (ataluren) or amlexanox. Following treatment, gene expression, protein levels and ciliogenesis were evaluated. The expression of intraflagellar transport protein IFT88 and G-protein coupled receptor SSTR3 was investigated as a readout of ciliary function. Findings mRNA expression was significantly increased in amlexanox-treated patient fibroblasts, and full-length BBS2 or ALMS1 protein expression was restored in PTC124- and amlexanox-treated fibroblasts. Treatment with TRIDs significantly improved ciliogenesis defects in BBS2 Y24*/R275* fibroblasts. Treatment recovered IFT88 expression and corrected SSTR3 mislocalisation in BBS2 Y24*/R275* and ALMS1 S1645*/S1645* fibroblasts, suggesting rescue of ciliary function. Interpretation The recovery of full-length BBS2 and ALMS1 expression and correction of anatomical and functional ciliary defects in BBS2 Y24*/R275* and ALMS1 S1645*/S1645* fibroblasts suggest TRIDs are a potential therapeutic option for the treatment of nonsense-mediated ciliopathies.

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Section: Discussionmentioning

confidence: 99%

Translational readthrough of ciliopathy genes BBS2 and ALMS1 restores protein, ciliogenesis and function in patient fibroblasts

Eintracht¹,

Forsythe

May-Simera³

et al. 2021

EBioMedicine

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“…BBS10 has been shown to participate in insulin signaling by direct interaction with the IR. Wang et al showed that insulin signaling was impaired in BBS1 and BBS10 human mutant fibroblasts, more severely in BBS10 mutated cells (Wang et al, 2021). These findings are consistent with the greater severity of insulin resistance in BBS10 patients than in BBS1 patients (Feuillan et al, 2011).…”

Section: The Extra‐ciliary Function Of the Chaperonin‐like Bbs Proteinsmentioning

confidence: 99%

“…Interestingly, BBS1 and BBS10 co‐immunoprecipitated with the IR and BBS10 mutations decreased IR autophosphorylation upon interaction with insulin, in human fibroblasts. Similarly, leptin signaling was deregulated in both BBS1 and BBS10 mutated hypothalamic derived neurons; whether BBS10 defects impaired leptin receptor (LR) trafficking via BBSome abnormalities, or it may contribute to the control of LR stability by itself has not been investigated (Wang et al, 2021).…”

Section: The Extra‐ciliary Function Of the Chaperonin‐like Bbs Proteinsmentioning

confidence: 99%

Bardet–Biedl syndrome: The pleiotropic role of the chaperonin‐like BBS6, 10, and 12 proteins

Gupta

D’Acierno

Zona

et al. 2022

American J of Med Genetics Pt C

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Bardet-Biedl syndrome (BBS) is a rare pleiotropic disorder known as a ciliopathy. Despite significant genetic heterogeneity, BBS1 and BBS10 are responsible for major diagnosis in western countries. It is well established that eight BBS proteins, namely BBS1, 2, 4, 5, 7, 8, 9, and 18, form the BBSome, a multiprotein complex serving as a regulator of ciliary membrane protein composition. Less information is available for BBS6, BBS10, and BBS12, three proteins showing sequence homology with the CCT/TRiC family of group II chaperonins. Even though their chaperonin function is debated, scientific evidence demonstrated that they are required for initial BBSome assembly in vitro. Recent studies suggest that genotype may partially predict clinical outcomes. Indeed, patients carrying truncating mutations in any gene show the most severe phenotype; moreover, mutations in chaperonin-like BBS proteins correlated with severe kidney impairment. This study is a critical review of the literature on genetics, expression level, cellular localization and function of BBS proteins, focusing primarily on the chaperonin-like BBS proteins, and aiming to provide some clues to understand the pathomechanisms of disease in this setting.

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“…Wang and colleagues recently published a work using induced pluripotent stem cell-derived (iPSC) neurons obtained from both BBS patients and controls where they show that mutations in BBS genes affect neurite outgrowth and neuronal energy homeostasis. Interestingly, BBS mutant iPSC-derived neurons presented elongated cilia [61]. Observing elongated cilia in a region of the brain that has been linked to the development of ASD conditions, like the striatum [62,63], suggests the possibility of cilia playing an active role in the development of these conditions.…”

Section: Discussionmentioning

confidence: 99%

Generation and characterization ofCcdc28bmutant mice links the Bardet-Biedl associated gene with social behavioral phenotypes

Fabregat

Niño

Pose

et al. 2021

Preprint

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CCDC28B (coiled-coil domain-containing protein 28B) was identified as a modifier in the ciliopathy Bardet-Biedl syndrome (BBS). Our previous work in cells and zebrafish showed that CCDC28B plays a role regulating cilia length in a mechanism that is not completely understood. Here we report the generation of a Ccdc28b mutant mouse using CRISPR/Cas9 (Ccdc28b mut). After confirming the depletion of Ccdc28b ;we performed a phenotypic characterization showing that Ccdc28b mut animals present a mild phenotype: i) do not present clear structural cilia affectation, although we did observe mild defects in cilia density and cilia length in some tissues, ii) reproduce normally, and iii) do not develop retinal degeneration or obesity, two hallmark features of reported BBS murine models. In contrast, Ccdc28b mut mice did show clear social interaction defects as well as stereotypical behaviors suggestive of autism spectrum disorder (ASD). This finding is indeed relevant regarding CCDC28B as a modifier of BBS since behavioral phenotypes have been documented in BBS. Importantly however, our data suggests a possible causal link between CCDC28B and ASD-like phenotypes that exceeds the context of BBS: filtering for rare deleterious variants, we found CCDC28B mutations in eight probands from the Simmons Simplex Collection cohort. Furthermore, a phenotypic analysis showed that CCDC28B mutation carriers present lower BMI and mild communication defects compared to a randomly selected sample of SSC probands. Thus, our results suggest that mutations in CCDC28B lead to mild autism-like features in mice and humans. Overall, this work reports a novel mouse model that will be key to continue evaluating genetic interactions in BBS, deciphering the contribution of CCDC28B to modulate the presentation of BBS phenotypes. In addition, our data underscores a novel link between CCDC28B and ASD-like phenotypes, providing a novel opportunity to further our understanding of the genetic, cellular, and molecular basis of ASD.

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Bardet-Biedl syndrome proteins regulate intracellular signaling and neuronal function in patient-specific iPSC-derived neurons

Cited by 36 publications

References 68 publications

Translational readthrough of ciliopathy genes BBS2 and ALMS1 restores protein, ciliogenesis and function in patient fibroblasts

Translational readthrough of ciliopathy genes BBS2 and ALMS1 restores protein, ciliogenesis and function in patient fibroblasts

Bardet–Biedl syndrome: The pleiotropic role of the chaperonin‐like BBS6, 10, and 12 proteins

Generation and characterization ofCcdc28bmutant mice links the Bardet-Biedl associated gene with social behavioral phenotypes

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