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Molecular and Human Genetics


  • José Badano, PhD (Head)
  • Florencia Irigoín, PhD (Research associate)
  • Victoria Prieto, PhD (Postdoctoral Fellow)
  • Magdalena Cárdenas, MSc (Postdoctoral FellowPhD student)
  • Paola Lepanto (PhD student)
  • Rossina Novas, Bach (PhD student)
  • Belén Torrado (MSc student)
  • Matías Fabregat (MSc student)




One protein in which we have been working is CCDC28B (coiled-coil domain containing protein 28b), a protein originally identified as a second site modifier of the BBS phenotype given that the mutation found in CCDC28B was not sufficient to cause BBS but did collaborate with mutations at bona fide BBS loci to modulate the penetrance and expressivity of the disorder [26]. Thus we started working in this protein of unknown function to both gain information regarding its role in cilia biology and to understand, at the cellular and molecular level, why it behaves as a modifier of BBS. Through a combination of bioinformatics, cellular and in vivo (zebrafish) studies we were able to determine that CCDC28B is a conserved protein restricted to metazoa that participates in the regulation of ciliary length. We showed that depletion of this protein both in cultured cells and zebrafish results in shortened cilia and thus ccdc28b morphant zebrafish embryos present with a number of cilia-associated phenotypes such as shortening of the body axis, smaller eyes, defects in the establishment of the left-right axis of symetry and hydrocephalus [27].

To understand the mechanism by which CCDC28B modulates cilia length we sought to identify proteins that physically interact with it. In a yeast two-hybrid screen we identify an interaction with the mTORC2 component SIN1. We were able to show that the CCDC28B/SIN1 interaction is relevant both in the context of cilia length regulation as well as modulating mTORC2. In the context of the mTOR complex our data showed that CCDC28B participates in its assembly and/or mediates its stability and thus, a depletion of CCDC28B results in decreased activity of the complex whereas its overexpression has the converse effect. Regarding the role of CCDC28B in cilia length regulation, we were able to show that this activity of the BBS modifier depends, at least in part, on its interaciont with SIN1 but independently of mTORC2 since i) sin1 morphant embryos, but not other mTORC2 component (rictor), present with shortened cilia, ii) ccdc28b and sin1 interact genetically and iii) overexpression of sin1 can partially ameliorate the cilia defect in ccdc28b morphant embryos [28]. Interestingly, mTORC2 dysfunction resulted in cilia-related phenotypes albeit not affecting cilia directly. One possibility that we are currently exploring is that mTORC2 dysfunction could contribute to the pathogenesis of cilia-associated defects through a “PCP-like” phenotype, thus potentially providing a cellular explanation to the observed modifier effect of CCDC28B. Therefore, while we keep studying CCDC28B/SIN1 to gain mechanistic insight into their role in cilia regulation (CSIC Grant), the study of this particular protein has open new avenues of research in the lab.

Our initial studies on BBS7, which led to the demonstration that at least some BBS proteins play extraciliary roles in the nucleus modulating gene transcription [24], resulted in a similar process in the lab leading to a new line of research. In this project, which is being guided by Dr. Irigoín, we are interested in understanding the process of protein targeting to the cilium focusing on proteins that can localize to both the cilium and nucleus. A growing number of reports in the literature are highlighting striking similarities in the process of nuclear and cilia protein import (for example see Ref. [29]. We are focusing on a number of proteins that shuttle between these two cellular compartments, including some of the BBSs, to understand whether they used similar mechanisms and if so, identify the signals that allow them to choose between destinations. To this end, we are working on an interdisciplinary collaboration with another unit at the IPMon (UByPA) where we plan to use a combination of cell/molecular biology and mass spectrometry to explore this cilia-nucleus connection (Intramural IPMon Grant).

More recently we have started working on another BBS protein, BBS4, since we have identified interesting protein interactors potentially linked to at least some of the BBS typical phenotypes. Our results have highlighted a role of BBS4 and other BBS proteins on intracellular trafficking, an area of research in which we became especially interested through a collaboration with Dr. NorannZaghloul at University of Maryland, Baltimore, USA, who has shown that the BBS proteins participate in the intracellular trafficking of the Notch receptor[25]. Lastly, through collaboration with Dr. Flavio Zolessi, we are studying the role of cilia during the formation and differentiation of neuronal cell types, in particular retinal ganglion cells (FCE Grant).

  1. Irigoin, F. and J.L. Badano, Keeping the balance between proliferation and differentiation: the primary cilium. Curr Genomics, 2011. 12(4): p. 285-297.
  2. Cardenas-Rodriguez, M. and J.L. Badano, Ciliary Biology: Understanding the Cellular and Genetic Basis of Human Ciliopathies. Am J Med Genet Part C Semin Med Genet, 2009. 151C: p. 263-280.
  3. Badano, J.L., et al., The Ciliopathies: An Emerging Class of Human Genetic Disorders. Annu Rev Genomics Hum Genet, 2006. 22: p. 125-148.
  4. Kim, S.K., et al., Planar Cell Polarity Acts Through Septins to Control Collective Cell Movement and Ciliogenesis. Science, 2010. 329: p. 1337-1340.
  5. Leitch, C.C., et al., Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet, 2008. 40: p. 443-448.
  6. Marion, V., et al., Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet–Biedl syndrome with situs inversus and insertional polydactyly. J Med Genet, 2012. 49: p. 317-321.
  7. Otto, E.A., et al., Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nat Genet, 2010. 42: p. 840-850.
  8. Scheidecker, S., et al., Exome sequencing of Bardet-Biedl syndrome patient identifies a null mutation in the BBSome subunit BBIP1 (BBS18). J Med Genet, 2014. 51(2): p. 132-6.
  9. Aldahmesh, M.A., et al., IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet-Biedl syndrome. Hum Mol Genet, 2014. 23(12): p. 3307-15.
  10. Ansley, S.J., et al., Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature, 2003. 425: p. 628-633.
  11. Blacque, O.E., et al., Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. Genes Dev, 2004. 18: p. 1630-1642.
  12. Fan, Y., et al., Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat Genet, 2004. 36: p. 989-993.
  13. Gerdes, J.M., et al., Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response. Nat Genet, 2007. 39: p. 1350-1360.
  14. Jin, H., et al., The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell, 2010. 141: p. 1208-1219.
  15. Kim, J.C., et al., The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet, 2004. 36: p. 462-470.
  16. Kim, J.C., et al., MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis. J Cell Sci, 2005. 118: p. 1007-1020.
  17. Li, J.B., et al., Comparative genomic identification of conserved flagellar and basal body proteins that includes a novel gene for Bardet-Biedl syndrome. Cell, 2004. 117: p. 541-552.
  18. Loktev, A.V., et al., A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell, 2008. 15: p. 854-865.
  19. Marion, V., et al., Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation. Proc Natl Acad Sci U S A, 2009. 10: p. 1820-1825.
  20. Nachury, M.V., et al., A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell, 2007. 129(6): p. 1201-1213.
  21. Ross, A.J., et al., Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat Genet, 2005. 37: p. 1135-1140.
  22. Wiens, C.J., et al., Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling. J Biol Chem, 2010. 285: p. 16218-16230.
  23. Zhang, Q., et al., BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes. Hum Mol Genet, 2012. 21: p. 1945-1953.
  24. Gascue, C., et al., Direct role of Bardet-Biedl syndrome proteins in transcriptional regulation. J Cell Sci, 2012. 125: p. 362-375.
  25. Leitch, C.C., et al., Basal body proteins regulate Notch signaling through endosomal trafficking. J Cell Sci, 2014. 127(Pt 11): p. 2407-19.
  26. Badano, J.L., et al., Dissection of epistasis in oligogenic Bardet-Biedl syndrome. Nature, 2006. 439: p. 326-330.
  27. Cardenas-Rodriguez, M., et al., Characterization of CCDC28B reveals its role in ciliogenesis and provides insight to understand its modifier effect on Bardet-Biedl syndrome. Hum Genet, 2013. 132(1): p. 91-105.
  28. Cardenas-Rodriguez, M., et al., The Bardet-Biedl syndrome-related protein CCDC28B modulates mTORC2 function and interacts with SIN1 to control cilia length independently of the mTOR complex. Hum Mol Genet, 2013. 22(20): p. 4031-42.
  29. Dishinger, J.F., et al., Ciliary entry of the kinesin-2 motor KIF17 is regulated by importin-beta2 and RanGTP. Nat Cell Biol, 2010. 12(7): p. 703-10.

Research lines

  • CCDC28B and the BBS proteins in theregulation of ciliogenesis and cilia length.
  • Cilia targeting: similaritieswiththe nuclear transportprocess.
  • BBS proteins in intracellulartrafficking: implicationsfor human disease.
  • Cilia in thedevelopment of the retina.



  1. Molecular Biology of the Cell International Course, January 2014, Institut Pasteur Paris, Paris, France (RossinaNovas).


  1. Internship in the Laboratory of Lucia Poggi, Dept. of Animal Physiology & Developmental Biology, COS, Heidelberg, Germany (Paola Lepanto).


  1. III LAZEN Meeting, April 11-13, Valparaíso, Chile (José Badano).
  2. 64thLindau Nobel Laureate Meeting, Lindau, Germany (Magdalena Cárdenas).
  3. Cilia 2014, Novembre 18th-21st, Institut Pasteur Paris, Paris, France (Paola Lepanto, FlorenciaIrigoín, José Badano).


  1. Master Fellowship – Belén Torrado – 2013-2015 – ANII
  2. Doctoral Fellowship – Paola Lepanto – 2013-2016 – ANII
  3. Master Fellowship – Matías Fabregat – 2014-2016 – ANII
  4. Fondo Clemente Estable – Dr. Flavio Zolessi – “Rol de las cilias y proceso de ciliogénesis durante la generación y diferenciación de neuronas en el sistema nervioso central de vertebrados.”- 2013-2015 – ANII
  5. CSIC Project – Florencia Irigoín – “Estudios funcionales y estructurales de CCDC28B, un modificador del Síndrome de Bardet-Biedl.” – 2013-2015 – I+D Program, CSIC, UDELAR
  6. Proyecto Transversal – Florencia Irigoín – “Protein sorting and transport to the ciliar and nuclear compartments: common and distinctive mechanisms” – 2013-2014 – IP Montevideo.


  1. ShigunovShigunov P, Sotelo-Silveira J, Stimamiglio MA, Kuligovski C, Irigoín F, BadanoJL, Munroe D, CorreaA, Dallagiovanna B. Ribonomicanalysis of human DZIP1 revealsitsinvolvement in ribonucleoproteincomplexes and stress granules (2014) BMC Molecular Biology, 15, art. no. 12. – IF: 2.057
  2. Leitch CC, Lodh S, Prieto-Echagüe V, Badano JL, Zaghloul NA. Basal body proteins regulate notch signaling through endosomal trafficking (2014) Journal of Cell Science, 127 (11), pp. 2391-2400. – IF: 5.325.