1. Developmental Biology

Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome

  1. Susanne Roosing
  2. Matan Hofree
  3. Sehyun Kim
  4. Eric Scott
  5. Brett Copeland
  6. Marta Romani
  7. Jennifer L Silhavy
  8. Rasim O Rosti
  9. Jana Schroth
  10. Tommaso Mazza
  11. Elide Miccinilli
  12. Maha S Zaki
  13. Kathryn J Swoboda
  14. Joanne Milisa-Drautz
  15. William B Dobyns
  16. Mohamed Mikati
  17. Faruk İncecik
  18. Matloob Azam
  19. Renato Borgatti
  20. Romina Romaniello
  21. Rose-Mary Boustany
  22. Carol L Clericuzio
  23. Stefano D'Arrigo
  24. Petter Strømme
  25. Eugen Boltshauser
  26. Franco Stanzial
  27. Marisol Mirabelli-Badenier
  28. Isabella Moroni
  29. Enrico Bertini
  30. Francesco Emma
  31. Maja Steinlin
  32. Friedhelm Hildebrandt
  33. Colin A Johnson
  34. Michael Freilinger
  35. Keith K Vaux
  36. Stacey B Gabriel
  37. Pedro Aza-Blanc
  38. Susanne Heynen-Genel
  39. Trey Ideker
  40. Brian D Dynlacht
  41. Ji Eun Lee
  42. Enza Maria Valente
  43. Joon Kim
  44. Joseph G Gleeson  Is a corresponding author
  1. Howard Hughes Medical Institute, The Rockefeller University, United States
  2. University of California, San Diego, United States
  3. Mendel Institute, Italy
  4. National Research Center, Egypt
  5. University of Utah School of Medicine, United States
  6. University of New Mexico, United States
  7. Seattle Children's Hospital, United States
  8. Duke Institute for Brain Sciences, Duke University Medical Center, United States
  9. Cukurova University Medical Faculty, Turkey
  10. Wah Medical College, Pakistan
  11. Scientific Institute IRCCS Eugenio Medea, Italy
  12. American University of Beirut Medical Center, Lebanon
  13. Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy
  14. Oslo University Hospital, Norway
  15. University Children's Hospital, Switzerland
  16. Regional Hospital of Bolzano, Italy
  17. Istituto G. Gaslini, Italy
  18. Bambino Gesù Children's Research Hospital, IRCCS, Italy
  19. Bambino Gesù Children's Hospital, IRCCS, Italy
  20. University Children's Hospital,, Switzerland
  21. Howard Hughes Medical Institute, Harvard Medical School, United States
  22. University of Leeds, St. James's University Hospital, United Kingdom
  23. Medical University Vienna, Austria
  24. Broad Institute of Harvard and Massachusetts Institute of Technology, United States
  25. Burnham Institute, United States
  26. New York University School of Medicine, United States
  27. Department of Pathology and Cancer Institute, Smilow Research Center, United States
  28. Sungkyunkwan University, Republic of Korea
  29. School of Medical Science and Engineering, Republic of Korea
https://doi.org/10.7554/eLife.06602
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Cite this article
  1. Susanne Roosing
  2. Matan Hofree
  3. Sehyun Kim
  4. Eric Scott
  5. Brett Copeland
  6. Marta Romani
  7. Jennifer L Silhavy
  8. Rasim O Rosti
  9. Jana Schroth
  10. Tommaso Mazza
  11. Elide Miccinilli
  12. Maha S Zaki
  13. Kathryn J Swoboda
  14. Joanne Milisa-Drautz
  15. William B Dobyns
  16. Mohamed Mikati
  17. Faruk İncecik
  18. Matloob Azam
  19. Renato Borgatti
  20. Romina Romaniello
  21. Rose-Mary Boustany
  22. Carol L Clericuzio
  23. Stefano D'Arrigo
  24. Petter Strømme
  25. Eugen Boltshauser
  26. Franco Stanzial
  27. Marisol Mirabelli-Badenier
  28. Isabella Moroni
  29. Enrico Bertini
  30. Francesco Emma
  31. Maja Steinlin
  32. Friedhelm Hildebrandt
  33. Colin A Johnson
  34. Michael Freilinger
  35. Keith K Vaux
  36. Stacey B Gabriel
  37. Pedro Aza-Blanc
  38. Susanne Heynen-Genel
  39. Trey Ideker
  40. Brian D Dynlacht
  41. Ji Eun Lee
  42. Enza Maria Valente
  43. Joon Kim
  44. Joseph G Gleeson
(2015)
Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome
eLife 4:e06602.
https://doi.org/10.7554/eLife.06602
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Abstract

Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide siRNA screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies.

Article and author information

Author details

  1. Susanne Roosing

    Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  2. Matan Hofree

    Department of Computer Science and Engineering, University of California, San Diego, San Diego, United States
    Competing interests
    No competing interests declared.

  3. Sehyun Kim

    Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  4. Eric Scott

    Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  5. Brett Copeland

    Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  6. Marta Romani

    IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy
    Competing interests
    No competing interests declared.

  7. Jennifer L Silhavy

    Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  8. Rasim O Rosti

    Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  9. Jana Schroth

    Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  10. Tommaso Mazza

    IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy
    Competing interests
    No competing interests declared.

  11. Elide Miccinilli

    IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy
    Competing interests
    No competing interests declared.

  12. Maha S Zaki

    Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo, Egypt
    Competing interests
    No competing interests declared.

  13. Kathryn J Swoboda

    Departments of Neurology and Pediatrics, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    No competing interests declared.

  14. Joanne Milisa-Drautz

    Department of Pediatric Genetics, University of New Mexico, Albuquerque, United States
    Competing interests
    No competing interests declared.

  15. William B Dobyns

    Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, United States
    Competing interests
    No competing interests declared.

  16. Mohamed Mikati

    Division of Pediatric Neurology, Department of Pediatrics, Duke Institute for Brain Sciences, Duke University Medical Center, Durham, United States
    Competing interests
    No competing interests declared.

  17. Faruk İncecik

    Department of Pediatric Neurology, Cukurova University Medical Faculty, Balcali, Turkey
    Competing interests
    No competing interests declared.

  18. Matloob Azam

    Department of Pediatrics and Child Neurology, Wah Medical College, Wah Cantt, Pakistan
    Competing interests
    No competing interests declared.

  19. Renato Borgatti

    Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy
    Competing interests
    No competing interests declared.

  20. Romina Romaniello

    Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy
    Competing interests
    No competing interests declared.

  21. Rose-Mary Boustany

    Departments of Pediatrics, Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
    Competing interests
    No competing interests declared.

  22. Carol L Clericuzio

    Division of Genetics/Dysmorphology, Dept. Pediatrics, University of New Mexico, Albuquerque, United States
    Competing interests
    No competing interests declared.

  23. Stefano D'Arrigo

    Developmental Neurology Division, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
    Competing interests
    No competing interests declared.

  24. Petter Strømme

    Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
    Competing interests
    No competing interests declared.

  25. Eugen Boltshauser

    Department of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland
    Competing interests
    No competing interests declared.

  26. Franco Stanzial

    Department of Pediatrics, Genetic Counselling Service, Regional Hospital of Bolzano, Bolzano, Italy
    Competing interests
    No competing interests declared.

  27. Marisol Mirabelli-Badenier

    Child Neuropsychiatry Unit, Department of Neurosciences and Rehabilitation, Istituto G. Gaslini, Genoa, Italy
    Competing interests
    No competing interests declared.

  28. Isabella Moroni

    Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
    Competing interests
    No competing interests declared.

  29. Enrico Bertini

    Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Research Hospital, IRCCS, Rome, Italy
    Competing interests
    No competing interests declared.

  30. Francesco Emma

    Division of Nephrology and Dialysis, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
    Competing interests
    No competing interests declared.

  31. Maja Steinlin

    University Children's Hospital,, Berne, Switzerland
    Competing interests
    No competing interests declared.

  32. Friedhelm Hildebrandt

    Division of Nephrology, Department of Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.

  33. Colin A Johnson

    Section of Ophthalmology and Neurosciences, Wellcome Trust Brenner Building, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds, United Kingdom
    Competing interests
    No competing interests declared.

  34. Michael Freilinger

    Neuropediatric group, Department of Paediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.

  35. Keith K Vaux

    Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  36. Stacey B Gabriel

    Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.

  37. Pedro Aza-Blanc

    High Content Screening Systems, Burnham Institute, La Jolla, United States
    Competing interests
    No competing interests declared.

  38. Susanne Heynen-Genel

    High Content Screening Systems, Burnham Institute, La Jolla, United States
    Competing interests
    No competing interests declared.

  39. Trey Ideker

    Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, United States
    Competing interests
    No competing interests declared.

  40. Brian D Dynlacht

    New York University School of Medicine, Department of Pathology and Cancer Institute, Smilow Research Center, New York, United States
    Competing interests
    No competing interests declared.

  41. Ji Eun Lee

    Samsung Genome Institute, Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea
    Competing interests
    No competing interests declared.

  42. Enza Maria Valente

    IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy
    Competing interests
    No competing interests declared.

  43. Joon Kim

    Korea Advanced Institute of Science and Technology, School of Medical Science and Engineering, Daejeon, Republic of Korea
    Competing interests
    No competing interests declared.

  44. Joseph G Gleeson

    Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    For correspondence
    jogleeson@rockefeller.edu
    Competing interests
    Joseph G Gleeson, Reviewing editor, eLife.

Ethics

Human subjects: Consenting and sampling was performed on both parents and all available genetically informative siblings to include affected and unaffected members, as well as extended family members if appropriate, consistent with IRB guidelines approved by the ethical committee (JGE-0853) and according to the Declaration of Helsinki.

Copyright

© 2015, Roosing et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Susanne Roosing
  2. Matan Hofree
  3. Sehyun Kim
  4. Eric Scott
  5. Brett Copeland
  6. Marta Romani
  7. Jennifer L Silhavy
  8. Rasim O Rosti
  9. Jana Schroth
  10. Tommaso Mazza
  11. Elide Miccinilli
  12. Maha S Zaki
  13. Kathryn J Swoboda
  14. Joanne Milisa-Drautz
  15. William B Dobyns
  16. Mohamed Mikati
  17. Faruk İncecik
  18. Matloob Azam
  19. Renato Borgatti
  20. Romina Romaniello
  21. Rose-Mary Boustany
  22. Carol L Clericuzio
  23. Stefano D'Arrigo
  24. Petter Strømme
  25. Eugen Boltshauser
  26. Franco Stanzial
  27. Marisol Mirabelli-Badenier
  28. Isabella Moroni
  29. Enrico Bertini
  30. Francesco Emma
  31. Maja Steinlin
  32. Friedhelm Hildebrandt
  33. Colin A Johnson
  34. Michael Freilinger
  35. Keith K Vaux
  36. Stacey B Gabriel
  37. Pedro Aza-Blanc
  38. Susanne Heynen-Genel
  39. Trey Ideker
  40. Brian D Dynlacht
  41. Ji Eun Lee
  42. Enza Maria Valente
  43. Joon Kim
  44. Joseph G Gleeson
(2015)
Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome
eLife 4:e06602.
https://doi.org/10.7554/eLife.06602

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https://doi.org/10.7554/eLife.06602

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    1. Developmental Biology

    TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23)

    Louise A Stephen, Hasan Tawamie ... Hanno J Bolz
    Research Article Updated

    Joubert syndrome (JBTS) is a severe recessive neurodevelopmental ciliopathy which can affect several organ systems. Mutations in known JBTS genes account for approximately half of the cases. By homozygosity mapping and whole-exome sequencing, we identified a novel locus, JBTS23, with a homozygous splice site mutation in KIAA0586 (alias TALPID3), a known lethal ciliopathy locus in model organisms. Truncating KIAA0586 mutations were identified in two additional patients with JBTS. One mutation, c.428delG (p.Arg143Lysfs*4), is unexpectedly common in the general population and may be a major contributor to JBTS. We demonstrate KIAA0586 protein localization at the basal body in human and mouse photoreceptors, as is common for JBTS proteins, and also in pericentriolar locations. We show that loss of TALPID3 (KIAA0586) function in animal models causes abnormal tissue polarity, centrosome length and orientation, and centriolar satellites. We propose that JBTS and other ciliopathies may in part result from cell polarity defects.