The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4

John A. Sayer, Edgar A. Otto, John F. O'Toole, Gudrun Nurnberg, Michael A. Kennedy, Christian Becker, Hans Christian Hennies, Juliana Helou, Massimo Attanasio, Blake V. Fausett, Boris Utsch, Hemant Khanna, Yan Liu, Iain Drummond, Isao Kawakami, Takehiro Kusakabe, Motoyuki Tsuda, Li Ma, Hwankyu Lee, Ronald G. LarsonSusan J. Allen, Christopher J. Wilkinson, Erich A. Nigg, Chengchao Shou, Concepcion Lillo, David S. Williams, Bernd Hoppe, Markus J. Kemper, Thomas Neuhaus, Melissa A. Parisi, Ian A. Glass, Marianne Petry, Andreas Kispert, Joachim Gloy, Athina Ganner, Gerd Walz, Xueliang Zhu, Daniel Goldman, Peter Nurnberg, Anand Swaroop, Michel R. Leroux, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

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Abstract

The molecular basis of nephronophthisis, the most frequent genetic cause of renal failure in children and young adults, and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome are poorly understood. Using positional cloning, we here identify mutations in the gene CEP290 as causing nephronophthisis. It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation. CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle-dependent manner and in connecting cilia of photoreceptors. Abrogation of its function in zebrafish recapitulates the renal, retinal and cerebellar phenotypes of Joubert syndrome. Our findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.

Original languageEnglish (US)
Pages (from-to)674-681
Number of pages8
JournalNature Genetics
Volume38
Issue number6
DOIs
StatePublished - Jun 2006

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Activating Transcription Factor 4
Centrosome
Retinal Degeneration
Kidney
Photoreceptor Connecting Cilium
Cystic Kidney Diseases
Chromosome Segregation
Proteins
Zebrafish
Renal Insufficiency
Cysts
Organism Cloning
Young Adult
Cell Cycle
Central Nervous System
Epithelial Cells
Phenotype
Mutation
Genes
Joubert syndrome 1

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Sayer, J. A., Otto, E. A., O'Toole, J. F., Nurnberg, G., Kennedy, M. A., Becker, C., ... Hildebrandt, F. (2006). The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nature Genetics, 38(6), 674-681. https://doi.org/10.1038/ng1786

The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. / Sayer, John A.; Otto, Edgar A.; O'Toole, John F.; Nurnberg, Gudrun; Kennedy, Michael A.; Becker, Christian; Hennies, Hans Christian; Helou, Juliana; Attanasio, Massimo; Fausett, Blake V.; Utsch, Boris; Khanna, Hemant; Liu, Yan; Drummond, Iain; Kawakami, Isao; Kusakabe, Takehiro; Tsuda, Motoyuki; Ma, Li; Lee, Hwankyu; Larson, Ronald G.; Allen, Susan J.; Wilkinson, Christopher J.; Nigg, Erich A.; Shou, Chengchao; Lillo, Concepcion; Williams, David S.; Hoppe, Bernd; Kemper, Markus J.; Neuhaus, Thomas; Parisi, Melissa A.; Glass, Ian A.; Petry, Marianne; Kispert, Andreas; Gloy, Joachim; Ganner, Athina; Walz, Gerd; Zhu, Xueliang; Goldman, Daniel; Nurnberg, Peter; Swaroop, Anand; Leroux, Michel R.; Hildebrandt, Friedhelm.

In: Nature Genetics, Vol. 38, No. 6, 06.2006, p. 674-681.

Research output: Contribution to journalArticle

Sayer, JA, Otto, EA, O'Toole, JF, Nurnberg, G, Kennedy, MA, Becker, C, Hennies, HC, Helou, J, Attanasio, M, Fausett, BV, Utsch, B, Khanna, H, Liu, Y, Drummond, I, Kawakami, I, Kusakabe, T, Tsuda, M, Ma, L, Lee, H, Larson, RG, Allen, SJ, Wilkinson, CJ, Nigg, EA, Shou, C, Lillo, C, Williams, DS, Hoppe, B, Kemper, MJ, Neuhaus, T, Parisi, MA, Glass, IA, Petry, M, Kispert, A, Gloy, J, Ganner, A, Walz, G, Zhu, X, Goldman, D, Nurnberg, P, Swaroop, A, Leroux, MR & Hildebrandt, F 2006, 'The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4', Nature Genetics, vol. 38, no. 6, pp. 674-681. https://doi.org/10.1038/ng1786
Sayer, John A. ; Otto, Edgar A. ; O'Toole, John F. ; Nurnberg, Gudrun ; Kennedy, Michael A. ; Becker, Christian ; Hennies, Hans Christian ; Helou, Juliana ; Attanasio, Massimo ; Fausett, Blake V. ; Utsch, Boris ; Khanna, Hemant ; Liu, Yan ; Drummond, Iain ; Kawakami, Isao ; Kusakabe, Takehiro ; Tsuda, Motoyuki ; Ma, Li ; Lee, Hwankyu ; Larson, Ronald G. ; Allen, Susan J. ; Wilkinson, Christopher J. ; Nigg, Erich A. ; Shou, Chengchao ; Lillo, Concepcion ; Williams, David S. ; Hoppe, Bernd ; Kemper, Markus J. ; Neuhaus, Thomas ; Parisi, Melissa A. ; Glass, Ian A. ; Petry, Marianne ; Kispert, Andreas ; Gloy, Joachim ; Ganner, Athina ; Walz, Gerd ; Zhu, Xueliang ; Goldman, Daniel ; Nurnberg, Peter ; Swaroop, Anand ; Leroux, Michel R. ; Hildebrandt, Friedhelm. / The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. In: Nature Genetics. 2006 ; Vol. 38, No. 6. pp. 674-681.
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abstract = "The molecular basis of nephronophthisis, the most frequent genetic cause of renal failure in children and young adults, and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome are poorly understood. Using positional cloning, we here identify mutations in the gene CEP290 as causing nephronophthisis. It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation. CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle-dependent manner and in connecting cilia of photoreceptors. Abrogation of its function in zebrafish recapitulates the renal, retinal and cerebellar phenotypes of Joubert syndrome. Our findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.",
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AU - Kennedy, Michael A.

AU - Becker, Christian

AU - Hennies, Hans Christian

AU - Helou, Juliana

AU - Attanasio, Massimo

AU - Fausett, Blake V.

AU - Utsch, Boris

AU - Khanna, Hemant

AU - Liu, Yan

AU - Drummond, Iain

AU - Kawakami, Isao

AU - Kusakabe, Takehiro

AU - Tsuda, Motoyuki

AU - Ma, Li

AU - Lee, Hwankyu

AU - Larson, Ronald G.

AU - Allen, Susan J.

AU - Wilkinson, Christopher J.

AU - Nigg, Erich A.

AU - Shou, Chengchao

AU - Lillo, Concepcion

AU - Williams, David S.

AU - Hoppe, Bernd

AU - Kemper, Markus J.

AU - Neuhaus, Thomas

AU - Parisi, Melissa A.

AU - Glass, Ian A.

AU - Petry, Marianne

AU - Kispert, Andreas

AU - Gloy, Joachim

AU - Ganner, Athina

AU - Walz, Gerd

AU - Zhu, Xueliang

AU - Goldman, Daniel

AU - Nurnberg, Peter

AU - Swaroop, Anand

AU - Leroux, Michel R.

AU - Hildebrandt, Friedhelm

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