title: Conserved Genetic Interactions between Ciliopathy Complexes Cooperatively Support Ciliogenesis and Ciliary Signaling.
abstract: Mutations in genes encoding cilia proteins cause human ciliopathies, diverse disorders affecting many tissues. Individual genes can be linked to ciliopathies with dramatically different phenotypes, suggesting that genetic modifiers may participate in their pathogenesis. The ciliary transition zone contains two protein complexes affected in the ciliopathies Meckel syndrome (MKS) and nephronophthisis (NPHP). The BBSome is a third protein complex, affected in the ciliopathy Bardet-Biedl syndrome (BBS). We tested whether mutations in MKS, NPHP and BBS complex genes modify the phenotypic consequences of one another in both C. elegans and mice. To this end, we identified TCTN-1, the C. elegans ortholog of vertebrate MKS complex components called Tectonics, as an evolutionarily conserved transition zone protein. Neither disruption of TCTN-1 alone or together with MKS complex components abrogated ciliary structure in C. elegans. In contrast, disruption of TCTN-1 together with either of two NPHP complex components, NPHP-1 or NPHP-4, compromised ciliary structure. Similarly, disruption of an NPHP complex component and the BBS complex component BBS-5 individually did not compromise ciliary structure, but together did. As in nematodes, disrupting two components of the mouse MKS complex did not cause additive phenotypes compared to single mutants. However, disrupting both Tctn1 and either Nphp1 or Nphp4 exacerbated defects in ciliogenesis and cilia-associated developmental signaling, as did disrupting both Tctn1 and the BBSome component Bbs1. Thus, we demonstrate that ciliary complexes act in parallel to support ciliary function and suggest that human ciliopathy phenotypes are altered by genetic interactions between different ciliary biochemical complexes.
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Yee
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Francesc R
authors.initials: FR
authors.lastname: Garcia-Gonzalo
authors.affiliation: School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Rachel V
authors.initials: RV
authors.lastname: Bowie
authors.affiliation: Department of Molecular Biology and Biochemistry and Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Li
authors.affiliation: School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Kennedy
authors.affiliation: Department of Physiology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Kaveh
authors.initials: K
authors.lastname: Ashrafi
authors.affiliation: School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Oliver E
authors.initials: OE
authors.lastname: Blacque
authors.affiliation: Department of Molecular Biology and Biochemistry and Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Michel R
authors.initials: MR
authors.lastname: Leroux
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Reiter
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002923:Cilia / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015398:Signal Transduction
chemical_list: D029742:Caenorhabditis elegans Proteins