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. Larson; Susan 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

doi:10.1038/ng1786

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 journal › Article › peer-review

475 Scopus citations

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 language	English (US)
Pages (from-to)	674-681
Number of pages	8
Journal	Nature genetics
Volume	38
Issue number	6
DOIs	https://doi.org/10.1038/ng1786
State	Published - Jun 2006

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/ng1786

Cite this

Sayer, J. A., Otto, E. A., O'Toole, J. F., Nurnberg, G., Kennedy, M. A., Becker, C., Hennies, H. C., Helou, J., Attanasio, M., Fausett, B. V., Utsch, B., Khanna, H., Liu, Y., Drummond, I., Kawakami, I., Kusakabe, T., Tsuda, M., Ma, L., Lee, H., ... 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

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

@article{89b6dfc17b90467380a851f13fb44c83,

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

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.",

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

year = "2006",

month = jun,

doi = "10.1038/ng1786",

language = "English (US)",

volume = "38",

pages = "674--681",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

TY - JOUR

T1 - The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4

AU - Sayer, John A.

AU - Otto, Edgar A.

AU - O'Toole, John F.

AU - Nurnberg, Gudrun

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

PY - 2006/6

Y1 - 2006/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33745230448&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745230448&partnerID=8YFLogxK

U2 - 10.1038/ng1786

DO - 10.1038/ng1786

M3 - Article

C2 - 16682973

AN - SCOPUS:33745230448

SN - 1061-4036

VL - 38

SP - 674

EP - 681

JO - Nature genetics

JF - Nature genetics

IS - 6

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this