Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein

Scott, C. Anthony; Marsden, Autumn N.; Rebagliati, Michael; Zhang, Qihong; Chamling, Xitiz; Searby, Charles; Baye, Lisa M.; Sheffield, Val C.; Slusarski, Diane C.

doi:10.1371/journal.pgen.1006936

Cited by 25 publications

(29 citation statements)

References 67 publications

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“…(2010) also reported that the BBS disruption causes phenotypes associated with planar cell polarity (PCP) defects in zebrafish; likewise, there are other studies that also showed evidence for similar axial phenotypes by in vivo loss of function methods in zebrafish 21,22 . However, other recent studies 37 do not report early developmental phenotypes typically associated with PCP pathway defects. These possible discrepancies could be attributed to behavior/mutagenic efficiency of the different MOs used.…”

Section: Discussionmentioning

confidence: 90%

Functional analysis of new human Bardet-Biedl syndrome loci specific variants in the zebrafish model

Castro-Sánchez

Suárez-Bregua

Novas

et al. 2019

Sci Rep

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The multiple genetic approaches available for molecular diagnosis of human diseases have made possible to identify an increasing number of pathogenic genetic changes, particularly with the advent of next generation sequencing (NGS) technologies. However, the main challenge lies in the interpretation of their functional impact, which has resulted in the widespread use of animal models. We describe here the functional modelling of seven BBS loci variants, most of them novel, in zebrafish embryos to validate their in silico prediction of pathogenicity. We show that target knockdown (KD) of known BBS (BBS1, BB5 or BBS6) loci leads to developmental defects commonly associated with ciliopathies, as previously described. These KD pleiotropic phenotypes were rescued by co-injecting human wild type (WT) loci sequence but not with the equivalent mutated mRNAs, providing evidence of the pathogenic effect of these BBS changes. Furthermore, direct assessment of cilia located in Kupffer’s vesicle (KV) showed a reduction of ciliary length associated with all the studied variants, thus confirming a deleterious effect. Taken together, our results seem to prove the pathogenicity of the already classified and unclassified new BBS variants, as well as highlight the usefulness of zebrafish as an animal model for in vivo assays in human ciliopathies.

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Section: Discussionmentioning

confidence: 90%

Functional analysis of new human Bardet-Biedl syndrome loci specific variants in the zebrafish model

Castro-Sánchez

Suárez-Bregua

Novas

et al. 2019

Sci Rep

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“…Interestingly, we have shown that BBS7, which interacts with CCDC28B 10 , enters the nucleus and modulates gene transcription through an interaction with RNF2, a member of the polycomb chromatin remodeling complex 43 . This finding was reinforced recently by a report showing that BBS6 actively translocates between the cytoplasm and nucleus and interacts with the SWI/SNF chromatin remodeling protein SMARCC1 thus affecting gene transcription 44 . In the case of SIN1, the other reported CCDC28B interacting protein linked to cilia length regulation 13 , there are at least five isoforms produced by alternative splicing that present a dynamic sub-cellular localization being found in the plasma membrane, cytoplasm, nucleus, and in the case of the shorter SIN1γ, the basal body 45 – 47 .…”

Section: Discussionmentioning

confidence: 65%

Kinesin 1 regulates cilia length through an interaction with the Bardet-Biedl syndrome related protein CCDC28B

Novas

Cárdenas-Rodríguez

Lepanto

et al. 2018

Sci Rep

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Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, polydactyly, renal disease and mental retardation. CCDC28B is a BBS-associated protein that we have previously shown plays a role in cilia length regulation whereby its depletion results in shortened cilia both in cells and Danio rerio (zebrafish). At least part of that role is achieved by its interaction with the mTORC2 component SIN1, but the mechanistic details of this interaction and/or additional functions that CCDC28B might play in the context of cilia remain poorly understood. Here we uncover a novel interaction between CCDC28B and the kinesin 1 molecular motor that is relevant to cilia. CCDC28B interacts with kinesin light chain 1 (KLC1) and the heavy chain KIF5B. Notably, depletion of these kinesin 1 components results in abnormally elongated cilia. Furthermore, through genetic interaction studies we demonstrate that kinesin 1 regulates ciliogenesis through CCDC28B. We show that kinesin 1 regulates the subcellular distribution of CCDC28B, unexpectedly, inhibiting its nuclear accumulation, and a ccdc28b mutant missing a nuclear localization motif fails to rescue the phenotype in zebrafish morphant embryos. Therefore, we uncover a previously unknown role of kinesin 1 in cilia length regulation that relies on the BBS related protein CCDC28B.

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“…BBS6 (or MKKS) is required for retrograde cellular transport and proper cilia functioning. The zebrafish bbs6 (mkks) morphants have shorter cilia of their Kupffer vesicles [107]. BBS10 and BBS12, localize to the primary cilia of human preadipocytes, where they carry Wnt and Hedgehog receptors [108].…”

Section: Bardet-biedl Syndromementioning

confidence: 99%

Ciliary Genes in Renal Cystic Diseases

Adamiok‐Ostrowska

Piekiełko-Witkowska

2020

Cells

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Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer.

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Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein

Cited by 25 publications

References 67 publications

Functional analysis of new human Bardet-Biedl syndrome loci specific variants in the zebrafish model

Functional analysis of new human Bardet-Biedl syndrome loci specific variants in the zebrafish model

Kinesin 1 regulates cilia length through an interaction with the Bardet-Biedl syndrome related protein CCDC28B

Ciliary Genes in Renal Cystic Diseases

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