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Characterization of CCDC28B reveals its role in ciliogenesis and provides insight to understand its modifier effect on Bardet–Biedl syndrome

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Abstract

Bardet–Biedl syndrome (BBS) is a genetically heterogeneous disorder that is generally inherited in an autosomal recessive fashion. However, in some families, trans mutant alleles interact with the primary causal locus to modulate the penetrance and/or the expressivity of the phenotype. CCDC28B (MGC1203) was identified as a second site modifier of BBS encoding a protein of unknown function. Here we report the first functional characterization of this protein and show it affects ciliogenesis both in cultured cells and in vivo in zebrafish. Consistent with this biological role, our in silico analysis shows that the presence of CCDC28B homologous sequences is restricted to ciliated metazoa. Depletion of Ccdc28b in zebrafish results in defective ciliogenesis and consequently causes a number of phenotypes that are characteristic of BBS and other ciliopathy mutants including hydrocephalus, left–right axis determination defects and renal function impairment. Thus, this work reports CCDC28B as a novel protein involved in the process of ciliogenesis whilst providing functional insight into the cellular basis of its modifier effect in BBS patients.

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Acknowledgments

We thank Paola Lepanto for her assistance in image analysis and the Badano and Beales laboratory members for discussions and technical help. This study was supported by ANII-Innova and the Genzyme Renal Innovations Program (GRIP) (JLB) and by a grant EU FP7 (SYSCILIA-241955) to PLB and DO. JLB, MC-R, MG, HR and FI are supported by the “Programa de Desarrollo de las Ciencias Básicas”, PEDECIBA, and by the Agencia Nacional de Investigación e Innovación (ANII), Uruguay. PLB is a Wellcome Trust Senior Research Fellow.

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Correspondence to Jose L. Badano.

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439_2012_1228_MOESM1_ESM.pdf

Supplementary material 1 (PDF 1057 kb) Fig. S1: Phylogenetic analysis of CCDC28B. PhyML maximum-likelihood tree of CCDC28B protein homologs present in eukaryotic UniProt reviewed genomes. Tip labels contain species names and UniProt identifiers. The bottom scale bar indicates average substitutions per site

439_2012_1228_MOESM2_ESM.pdf

Supplementary material 2 (PDF 5991 kb) Fig. S2: Full MSA alignment. Complete alignment of all available CCDC28 sequences

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Supplementary material 3 (FASTA 101 kb)

Supplementary material 3 (TREE 9 kb)

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Cardenas-Rodriguez, M., Osborn, D.P.S., Irigoín, F. et al. Characterization of CCDC28B reveals its role in ciliogenesis and provides insight to understand its modifier effect on Bardet–Biedl syndrome. Hum Genet 132, 91–105 (2013). https://doi.org/10.1007/s00439-012-1228-5

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