Joubert syndrome is a rare and severe neurodevelopmental disease in which two parts of the brain called the cerebellar vermis and brainstem do not develop properly. The disease is caused by defects in the formation of small projections from the surface of cells, called cilia, which are essential for signalling processes inside cells. Mutations in at least 25 genes are known to cause Joubert syndrome, and all encode proteins that create or maintain cilia. However, these mutations account for only half of the cases that have been studied, which indicates that mutations in other genes may also cause Joubert syndrome.

Here, Stephen et al. used genetic techniques called ‘homozygosity mapping’ and ‘whole-exome sequencing’ to search for other mutations that might cause the disease. They found that mutations in a gene encoding a protein called KIAA0586 also cause Joubert syndrome in humans. One of these mutations (c.428delG) is unexpectedly common in the healthy human population. It might be a major contributor to Joubert syndrome, and the manifestation of Joubert syndrome in individuals with this mutation might depend on the presence and nature of other mutations in KIAA0586 and in other genes.

The TALPID3 protein in chickens and other ‘model’ animals is the equivalent of human KIAA0586. A loss of TALPID3 protein in animals has been shown to stop cilia from forming. This protein is found in a structure called the basal body, which is part of a larger structure called the centrosome that anchors cilia to the cell. Here, Stephen et al. show that this is also true in mouse and human eye cells.

Further experiments using chicken embryos show that a loss of the TALPID3 protein alters the location of centrosomes inside cells. TALPID3 is also required for cells and organs to develop the correct polarity, that is, directional differences in their structure and shape. The centrosomes of chicken brain cells that lacked TALPID3 were poorly positioned at the cell surface and abnormally long, which is likely responsible for the cilia failing to form.

Stephen et al.'s findings suggest that KIAA0586 is also important for human development through its ability to control the centrosome. Defects in TALPID3 have a more severe effect on animal models than many of the identified KIAA0586 mutations have on humans. Therefore, the next step in this research is to find a more suitable animal in which to study the role of this protein, which may inform efforts to develop treatments for Joubert syndrome.

Joubert syndrome (JBTS) is a rare ciliopathy characterized by a specific midhindbrain malformation presenting as ‘molar tooth sign’ on axial MRI. Patients typically have a perturbed respiratory pattern in the neonatal period and pronounced psychomotor delay. Depending on the genetic subtype, there may be additional retinal degeneration, nephronophthisis, liver fibrosis, and skeletal abnormalities (such as polydactyly). JBTS is genetically heterogeneous, with recessive mutations reported in more than 20 genes encoding proteins related to the function of cilia and associated structures (Romani et al., 2013; Bachmann-Gagescu et al., 2015).

Cilia are axoneme-based organelles which protrude into the extracellular milieu, anchored to the cell by a modified centriole (basal body). They are present in virtually every cell type (Christensen et al., 2007). Non-motile ‘primary’ cilia play essential roles in mechanotransduction, chemosensation, and intracellular signal transduction, including Hedgehog (Hh), PDGFα, and WNT pathways, in embryonic development and adult tissue homeostasis (Goetz and Anderson, 2010). In addition, highly modified and specialized cilia constitute the light-sensitive outer segments of retinal photoreceptor cells. Dysfunction of cilia, centrioles of basal bodies, and centrosomes can lead to a spectrum of developmental single- or multi-organ disorders termed ‘ciliopathies’ (Bettencourt-Dias et al., 2011).

KIAA0586 (TALPID3; MIM #610178, MIM #000979-9031) is essential for vertebrate development and ciliogenesis. The KIAA0586 (TALPID3) protein is localized at the centrosome in human, chicken, mouse, and zebrafish cells (Yin et al., 2009; Ben et al., 2011; Wu et al., 2014), and in particular, at the distal end of the mother centriole—the basal body of cilia (Kobayashi et al., 2014a). In model organisms, KIAA0586 null mutations cause failure of basal body docking and loss of cilia, leading to early embryonic lethal phenotypes (Davey et al., 2006; Bangs et al., 2011; Ben et al., 2011; Stephen et al., 2013). KIAA0586 (TALPID3) binding partners include PCM1, Cep120, and CP110, which interact with a known JBTS protein, CEP290 (Tsang and Dynlacht, 2013).

Here, we report three JBTS families with loss-of-function mutations in KIAA0586. Using animal models, we demonstrate that TALPID3 (KIAA0586) is not only essential for transduction of Hedgehog signaling but plays an important role in centrosomal localization, orientation, and length. Finally, and beyond its established requirement for ciliogenesis, TALPID3 (KIAA0586) plays a key role in cell and tissue polarity.

JBTS is a genetically heterogeneous condition, caused by mutations in several genes related to the structure and function of cilia (Romani et al., 2013). Through homozygosity mapping and WES, we identified a novel disease locus (JBTS23), defined by mutations in the KIAA0586 gene, encoding a centrosomal protein (Andersen et al., 2003) (Figure 1), which is supported by simultaneous concurrent studies (Bachmann-Gagescu et al., 2015; Roosing et al., 2015). We used Talpid3/TALPID3^−/− mouse and chicken models to understand the corresponding pathomechanisms causing the phenotypes of these patients and discovered centrosome abnormalities and loss of cell polarity.

We confirm localization of KIAA0586 at centrosomal structures at the basal bodies and the adjacent daughter centrioles of primary cilia of mouse and human photoreceptor cells as well as in pericentriolar regions (Figure 2). KIAA0586 has previously been associated with recessive ciliopathy phenotypes in mouse (Bangs et al., 2011; Davey et al., 2014), chicken (Davey et al., 2006; Davey et al., 2007) and zebrafish (Ben et al., 2011). These animal models have either naturally occurring or induced 5′ mutations which disrupt an essential coiled-coil domain, resulting in loss of protein function, consecutive loss of Hh signaling and early embryonic lethality. The talpid³ chicken is a thoroughly examined animal model with polydactyly, holoprosencephaly, abnormal neural tube patterning, polycystic kidneys, liver fibrosis, short ribs, and endochondral bones with defective ossification (Lewis et al., 1999; Buxton et al., 2004; Davey et al., 2006; Davey et al., 2014).

The c.428delG (p.Arg143Lysfs*4) mutation was identified in heterozygous state in patient MD1, in trans to a nonsense mutation (Figure 1B), and in a patient G2 who is also heterozygous for a KIF7 (JBTS12) frameshift mutation and variants in three other known ciliopathy genes (Figure 1C) (Dafinger et al., 2011). Our experiments did not indicate epistatic interaction between KIAA0586 and KIF7, and a secondary occult mutation in either gene cannot be excluded. The c.428delG mutation results in a premature termination codon in five human KIAA0586 isoforms, causing either a major protein truncation 5′ to the essential coiled-coil domain or NMD. It is comparable to the talpid³ chicken loss-of-function mutation which introduces a frameshift in the orthologous region (Figure 1F). The c.428delG mutation is annotated in dbSNP (rs534542684), and its MAF in the general population is surprisingly high (0.39%, 378 out of 96,534 alleles in the ExAC db), reminiscent of the most common deafness (c.35delG in GJB2; 0.60% in the ExAC database) or cystic fibrosis (p.Phe508del in CFTR; 0.67% in the ExAC database) mutation. In two concurrent studies reporting KIAA0586 mutations in patients with JBTS, c.428delG represented the most prevalent mutation (Bachmann-Gagescu et al., 2015; Roosing et al., 2015). While c.428delG was clearly enriched in patients with biallelic KIAA0586 mutations in both studies (present in 20 of 24 such patients), only two were homozygous. Despite its commonness, c.428delG was neither observed in homozygous state in healthy individuals in the TGP, ESP, or ExAC databases. Such rarity of homozygosity could indicate that it causes embryonic lethality, early death or severe illness leading to underrepresentation of the respective samples. Embryonic lethality in talpid³ chicken and Talpid3^−/− knockout mice would support such an interpretation. On the other hand, c.428delG was not found in a simultaneous study that reports biallelic KIAA0586 mutations in early lethal ciliopathies (Alby et al., 2015). Of note, a very recent study on rare human knockouts identified in the genomes of 2636 healthy Icelanders lists one individual of 57 years with homozygosity for c.428delG (Sulem et al., 2015). This could either be due to protective modifiers or a low mutational load in the ciliome of the respective person. Assuming the latter, c.428delG_KIAA0586 could represent a hypomorphic allele that increases susceptibility to develop JBTS, with more severe mutations required either in trans (in heterozygous carriers, as in most patients reported by Bachmann-Gagescu et al. (2015); Roosing et al. (2015)), or in other genes (in homozygous carriers) for disease manifestation. The presence of a heterozygous potentially deleterious C5orf42 (JBTS17) variant in the only c.428delG_KIAA0586-homozygous patient reported by Bachmann-Gagescu et al. (2015), and the co-occurence of such variants in four ciliopathy genes in patient G2 (including a truncation in the JBTS gene KIF7) support the categorization of c.428delG_KIAA0586 as a hypomorphic mutation of incomplete penetrance. Of note, no secondary KIAA0586 mutation was identified in c.428delG-heterozygous JBTS patients in the two other studies (Bachmann-Gagescu et al., 2015; Roosing et al., 2015), which could be due to the contribution of other genes.

The homozygous mutations c.2414-1G>C (Family 1) and c.2512C>T (p.Arg838*, Family 2) would not disrupt the 5′ functionally essential coiled-coil domain in the consecutive KIAA0586 protein, and partial function may be maintained (possibly due to preserved, albeit truncated, KIAA0586 protein). We have shown that KIAA0586 has several functions in the centriole, and this may be mediated by different protein residues.

The occurrence of retinal degeneration in JBTS depends on the genetic subtype, but is variable even within a family. The localization of KIAA0586 at the ciliary base of retinal photoreceptor cells corresponds to other JBTS proteins. Proteins of the periciliary compartment at the base of the photoreceptor cilium are thought to be critical for the handover of cargo from the dynein-mediated transport through the inner segment to the kinesin-powered anterograde intraflagellar transport in the ciliary compartment (Roepman and Wolfrum, 2007; Sedmak and Wolfrum, 2010). KIAA0586 may be part of the protein networks implicated in these processes. The lack of retinal disease in the patients described herein may be due to the less strongly developed structure of the distal appendages and/or the possible functional redundancy in the cilia of retinal photoreceptor cells. Nevertheless, patients with KIAA0586-related JBTS should be investigated for signs of retinal degeneration, and given that mutations in the JBTS gene CEP290 may cause non-syndromic Leber congenital amaurosis (den Hollander et al., 2006), KIAA0586 represents a candidate gene for isolated retinopathies.

Loss of KIAA0586 (TALPID3) function in animal models results in a failure to produce both primary and motile cilia. Previously, it has been suggested that this is due to a failure of the centrosome to migrate apically or dock at the plasma membrane (Yin et al., 2009; Stephen et al., 2013). The subsequent failure of cilia formation results in abnormal Hh signaling and disrupted GLI processing (Davey et al., 2006). Most patients with KIAA0586-related JBTS exhibit few classical Hh phenotypes such as polydactyly (this study, Bachmann-Gagescu et al., 2015; Roosing et al., 2015), unlike the corresponding mouse, chicken, and zebrafish models (Davey et al., 2006; Bangs et al., 2011; Ben et al., 2011). We show that, independent of Hh signaling, cell and tissue polarity are disrupted upon loss of TALPID3. JBTS is characterized by cerebellar hypoplasia and loss of decussation of neuronal projections from the cerebellum (Romani et al., 2013). While Hh signaling is required for controlling the growth of the embryonic cerebellar primordia (Lewis et al., 2004), the failure of decussation has been proposed to result from defective axonal guidance (Romani et al., 2013), a process depending on centrosome-guided cell polarity (Solecki et al., 2006). Furthermore, we have shown that in inner ear HCs, cell polarity and ciliogenesis, albeit closely linked, are differentially affected in talpid³ cells. Thus, loss of decussation may reflect loss of polarity.

We propose that KIAA0586 exerts a role in intracellular trafficking and cell polarity distinct from its role in docking of the centriole. Talpid³ cells have abnormal microtubule dynamics (Yin et al., 2009). Microtubules are required for the recruitment of satellites and proteins in the distal centriole (Kim et al., 2008; Schmidt et al., 2009), a process known to be impaired by loss of KIAA0586. Abnormal cell polarity in talpid³ cells may be due to the effect of TALPID3 on microtubule dynamics and a direct role in centrosome organization: microtubules are essential for intracellular trafficking, cellular structure, and polarity. We have shown that localization of the centrosome, mitochondria, and Golgi is disrupted in talpid³ cells. Moreover, Rab8, a GTPase which binds to the Golgi and is required for vesicular trafficking and ciliogenesis (Nachury et al., 2007; Henry and Sheff, 2008; Feng et al., 2012), is mislocalized in KIAA0586-depleted cells (Kobayashi et al., 2014a). In JBTS patients with mutations in AHI1 (JBTS3), encoding an interactor of RAB8 (Hsiao et al., 2009), non-ciliary trafficking from the Golgi and ciliogenesis are impaired. Of note, Golgi mislocalization in the talpid³ choroid plexus is similar to what has been observed in Ahi1^−/− mice (Hsiao et al., 2009). This suggests a similar pathogenesis of JBTS23 and JBTS3, with defective cell polarity, intracellular trafficking, and Hh signaling.

KIAA0586 interacts with CP110 and Cep120 (Kobayashi et al., 2014a), distal centriolar proteins implicated in centriole duplication and maturation, and ciliogenesis. The predominant expression of Cep120 on the daughter centriole throughout most of the cell cycle depends on Kiaa0586, as indicated by high expression of Cep120 on both centrioles and absence of CP110 from the mother centriole prior to ciliogenesis in Talpid3^−/− cells (Spektor et al., 2007). Although equal expression of KIAA0586 on the mother and daughter centrioles has been reported (this study, Kobayashi et al., 2014a); there is evidence that KIAA0586 predominantly localizes at the mother centriole (Wu et al., 2014). In addition, loss of chicken KIAA0586 (TALPID3) causes centriole elongation whereas overexpression of Cep120 causes elongation of the mother centriole, suggesting that KIAA0586 (TALPID3) may control centriole length through depletion or suppression of Cep120 on the mother centriole. Similarly, depletion of CP110 also increases centriole length (Schmidt et al., 2009), suggesting that KIAA0586 regulates centriolar length through controlling CP110 localization and centriolar capping of the distal mother centriole. Loss of other centriolar proteins, such as OFD1, likewise results in elongated centrioles and loss of distal appendages (Singla et al., 2010). Based on the colocalization of KIAA0586, CP110, and Cep164, it has been proposed that KIAA0586 regulates ciliary vesicle docking adjacent to Cep164 localization (Kobayashi et al., 2014a), but not distal appendage formation itself, and this is supported by evidence from human patient KIAA0586^−/− cells which show Cep164 within the distal centriole (Alby et al., 2015). We also find evidence for a vesicle docking defect, demonstrated by an increase in centriolar satellites. However, we propose that KIAA0586 loss primarily causes abnormal distal appendages and impaired Cep164 localization, similar to what can be observed in OFD1 mutants (Singla et al., 2010). In addition, determination of Cep164 expression in cells of highly polarized tissue demonstrates a further centriolar defect not easily distinguished in in vitro assays—the loss of centriole orientation to the apical membrane of the cell. Whether this defect is due to the depletion of KIAA0586 from the centriole or impairment of another function of KIAA0586 in pericentriolar regions or cytoskeleton remains to be elucidated.

We have identified KIAA0586 as a novel gene for JBTS, and we propose that it is not only required for ciliogenesis, but also to establish cell and thus tissue polarity. JBTS23, and possibly other JBTS subtypes, may result from impairment of both functions.

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Author details

1. Louise A Stephen

   Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom

   Contribution

   LAS, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0001-6795-0383

2. Hasan Tawamie

   Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

   Contribution

   HT, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

3. Gemma M Davis

   Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom

   Contribution

   GMD, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

4. Lars Tebbe

   Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany

   Contribution

   LT, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

5. Peter Nürnberg

   1. Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
   2. Cologne Cluster of Excellence, University of Cologne, Cologne, Germany

   Contribution

   PN, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

6. Gudrun Nürnberg

   Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

   Contribution

   GN, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

7. Holger Thiele

   Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

   Contribution

   HT, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

8. Michaela Thoenes

   Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany

   Contribution

   MT, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

9. Eugen Boltshauser

   Department of Paediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland

   Contribution

   EB, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

10. Steffen Uebe

    Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Contribution

    SU, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The authors declare that no competing interests exist.

11. Oliver Rompel

    Institute of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Contribution

    OR, Acquisition of data

    Competing interests

    The authors declare that no competing interests exist.

12. André Reis

    Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Contribution

    AR, Conception and design, Drafting or revising the article

    Competing interests

    The authors declare that no competing interests exist.

13. Arif B Ekici

    Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Contribution

    ABE, Acquisition of data, Drafting or revising the article

    Competing interests

    The authors declare that no competing interests exist.

14. Lynn McTeir

    Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom

    Contribution

    LMT, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The authors declare that no competing interests exist.

15. Amy M Fraser

    Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom

    Contribution

    AMF, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The authors declare that no competing interests exist.

16. Emma A Hall

    Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom

    Contribution

    EAH, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The authors declare that no competing interests exist.

17. Pleasantine Mill

    Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom

    Contribution

    PM, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The authors declare that no competing interests exist.

18. Nicolas Daudet

    UCL Ear Institute, University College London, London, United Kingdom

    Contribution

    ND, Conception and design, Acquisition of data, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    The authors declare that no competing interests exist.

19. Courtney Cross

    School of Osteopathic Medicine, A.T. Still University, Mesa, United States

    Contribution

    CC, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    The authors declare that no competing interests exist.

20. Uwe Wolfrum

    Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany

    Contribution

    UW, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    The authors declare that no competing interests exist.

21. Rami Abou Jamra

    1. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
    2. Centogene, Rostock, Germany
    3. Institute of Human Genetics, Leipzig University, Leipzig, Germany

    Contribution

    RAJ, Clinical examination of patients, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

    Contributed equally with

    Megan G Davey and Hanno J Bolz

    Competing interests

    The authors declare that no competing interests exist.

22. Megan G Davey

    Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom

    Contribution

    MGD, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

    Contributed equally with

    Rami Abou Jamra and Hanno J Bolz

    For correspondence

    megan.davey@roslin.ed.ac.uk

    Competing interests

    The authors declare that no competing interests exist.

23. Hanno J Bolz

    1. Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany
    2. Bioscientia Center for Human Genetics, Bioscientia International Business, Ingelheim am Rhein, Germany

    Contribution

    HJB, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

    Contributed equally with

    Rami Abou Jamra and Megan G Davey

    For correspondence

    hanno.bolz@uk-koeln.de

    Competing interests

    The authors declare that no competing interests exist.

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