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

Susanne Roosing; Matan Hofree; Sehyun Kim; Eric Scott; Brett Copeland; Marta Romani; Jennifer L. Silhavy; Rasim O. Rosti; Jana Schroth; Tommaso Mazza; Elide Miccinilli; Maha S. Zaki; Kathryn J. Swoboda; Joanne Milisa-Drautz; William B. Dobyns; Mohamed Mikati; Faruk İncecik; Matloob Azam; Renato Borgatti; Romina Romaniello; Rose Mary Boustany; Carol L. Clericuzio; Stefano D’Arrigo; Petter Strømme; Eugen Boltshauser; Franco Stanzial; Marisol Mirabelli-Badenier; Isabella Moroni; Enrico Bertini; Francesco Emma; Maja Steinlin; Friedhelm Hildebrandt; Colin A. Johnson; Michael Freilinger; Keith K. Vaux; Stacey B. Gabriel; Pedro Aza-Blac; Susanne Genel Heynen; Trey Ideker; Brian D. Dynlacht; Ji Eun Lee; Enza Maria Valente; Joon Kim; Joseph G. Gleeson

doi:10.7554/eLife.06602

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

Susanne Roosing, Matan Hofree, Sehyun Kim, Eric Scott, Brett Copeland, Marta Romani, Jennifer L. Silhavy, Rasim O. Rosti, Jana Schroth, Tommaso Mazza, Elide Miccinilli, Maha S. Zaki, Kathryn J. Swoboda, Joanne Milisa-Drautz, William B. Dobyns, Mohamed Mikati, Faruk İncecik, Matloob Azam, Renato Borgatti, Romina RomanielloRose Mary Boustany, Carol L. Clericuzio, Stefano D’Arrigo, Petter Strømme, Eugen Boltshauser, Franco Stanzial, Marisol Mirabelli-Badenier, Isabella Moroni, Enrico Bertini, Francesco Emma, Maja Steinlin, Friedhelm Hildebrandt, Colin A. Johnson, Michael Freilinger, Keith K. Vaux, Stacey B. Gabriel, Pedro Aza-Blac, Susanne Genel Heynen, Trey Ideker, Brian D. Dynlacht, Ji Eun Lee, Enza Maria Valente, Joon Kim, Joseph G. Gleeson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

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.

Original language	English
Article number	e06602
Pages (from-to)	1-37
Number of pages	37
Journal	eLife
Volume	4
Issue number	MAY
DOIs	https://doi.org/10.7554/eLife.06602
State	Published - 30 May 2015
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2015, eLife Sciences Publications Ltd. All rights reserved.

Keywords

Ciliopathy
High-content screen
Joubert syndrome
KIAA0586
SiRNA
Talpid3

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10.7554/eLife.06602

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Roosing, S., Hofree, M., Kim, S., Scott, E., Copeland, B., Romani, M., Silhavy, J. L., Rosti, R. O., Schroth, J., Mazza, T., Miccinilli, E., Zaki, M. S., Swoboda, K. J., Milisa-Drautz, J., Dobyns, W. B., Mikati, M., İncecik, F., Azam, M., Borgatti, R., ... Gleeson, J. G. (2015). Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome. eLife, 4(MAY), 1-37. Article e06602. https://doi.org/10.7554/eLife.06602

@article{87a41cc373214c6c99bbf5016ab539ed,

title = "Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome",

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.",

keywords = "Ciliopathy, High-content screen, Joubert syndrome, KIAA0586, SiRNA, Talpid3",

author = "Susanne Roosing and Matan Hofree and Sehyun Kim and Eric Scott and Brett Copeland and Marta Romani and Silhavy, {Jennifer L.} and Rosti, {Rasim O.} and Jana Schroth and Tommaso Mazza and Elide Miccinilli and Zaki, {Maha S.} and Swoboda, {Kathryn J.} and Joanne Milisa-Drautz and Dobyns, {William B.} and Mohamed Mikati and Faruk İncecik and Matloob Azam and Renato Borgatti and Romina Romaniello and Boustany, {Rose Mary} and Clericuzio, {Carol L.} and Stefano D{\textquoteright}Arrigo and Petter Str{\o}mme and Eugen Boltshauser and Franco Stanzial and Marisol Mirabelli-Badenier and Isabella Moroni and Enrico Bertini and Francesco Emma and Maja Steinlin and Friedhelm Hildebrandt and Johnson, {Colin A.} and Michael Freilinger and Vaux, {Keith K.} and Gabriel, {Stacey B.} and Pedro Aza-Blac and Heynen, {Susanne Genel} and Trey Ideker and Dynlacht, {Brian D.} and Lee, {Ji Eun} and Valente, {Enza Maria} and Joon Kim and Gleeson, {Joseph G.}",

year = "2015",

month = may,

day = "30",

doi = "10.7554/eLife.06602",

language = "אנגלית",

volume = "4",

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Roosing, S, Hofree, M, Kim, S, Scott, E, Copeland, B, Romani, M, Silhavy, JL, Rosti, RO, Schroth, J, Mazza, T, Miccinilli, E, Zaki, MS, Swoboda, KJ, Milisa-Drautz, J, Dobyns, WB, Mikati, M, İncecik, F, Azam, M, Borgatti, R, Romaniello, R, Boustany, RM, Clericuzio, CL, D’Arrigo, S, Strømme, P, Boltshauser, E, Stanzial, F, Mirabelli-Badenier, M, Moroni, I, Bertini, E, Emma, F, Steinlin, M, Hildebrandt, F, Johnson, CA, Freilinger, M, Vaux, KK, Gabriel, SB, Aza-Blac, P, Heynen, SG, Ideker, T, Dynlacht, BD, Lee, JE, Valente, EM, Kim, J & Gleeson, JG 2015, 'Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome', eLife, vol. 4, no. MAY, e06602, pp. 1-37. https://doi.org/10.7554/eLife.06602

TY - JOUR

T1 - Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome

AU - Roosing, Susanne

AU - Hofree, Matan

AU - Kim, Sehyun

AU - Scott, Eric

AU - Copeland, Brett

AU - Romani, Marta

AU - Silhavy, Jennifer L.

AU - Rosti, Rasim O.

AU - Schroth, Jana

AU - Mazza, Tommaso

AU - Miccinilli, Elide

AU - Zaki, Maha S.

AU - Swoboda, Kathryn J.

AU - Milisa-Drautz, Joanne

AU - Dobyns, William B.

AU - Mikati, Mohamed

AU - İncecik, Faruk

AU - Azam, Matloob

AU - Borgatti, Renato

AU - Romaniello, Romina

AU - Boustany, Rose Mary

AU - Clericuzio, Carol L.

AU - D’Arrigo, Stefano

AU - Strømme, Petter

AU - Boltshauser, Eugen

AU - Stanzial, Franco

AU - Mirabelli-Badenier, Marisol

AU - Moroni, Isabella

AU - Bertini, Enrico

AU - Emma, Francesco

AU - Steinlin, Maja

AU - Hildebrandt, Friedhelm

AU - Johnson, Colin A.

AU - Freilinger, Michael

AU - Vaux, Keith K.

AU - Gabriel, Stacey B.

AU - Aza-Blac, Pedro

AU - Heynen, Susanne Genel

AU - Ideker, Trey

AU - Dynlacht, Brian D.

AU - Lee, Ji Eun

AU - Valente, Enza Maria

AU - Kim, Joon

AU - Gleeson, Joseph G.

PY - 2015/5/30

Y1 - 2015/5/30

N2 - 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.

AB - 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.

KW - Ciliopathy

KW - High-content screen

KW - Joubert syndrome

KW - KIAA0586

KW - SiRNA

KW - Talpid3

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DO - 10.7554/eLife.06602

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AN - SCOPUS:84930622375

SN - 2050-084X

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JO - eLife

JF - eLife

IS - MAY

M1 - e06602

ER -

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

Abstract

Bibliographical note

Keywords

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