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


The molecular basis of nephronophthisis1, 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 syndrome2 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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Figure 1: Positional cloning of the CEP290 gene as mutated in NPHP6/SLSN6/JBTS6.
Figure 2: NPHP6 localizes to the centrosome during interphase, independent of microtubule polymerization.
Figure 3: nphp6 expression pattern and targeted knockdown of zebrafish nphp6 are consistent with the kidney, cerebellar and retinal phenotypes of Joubert syndrome.
Figure 4: The cep290 homolog of C. intestinalis shows a dynamic developmental expression pattern and results in developmental arrest upon targeted knockdown.
Figure 5: NPHP6 partially localizes to the nucleus, directly interacts with ATF4 and induces its transcriptional activation.

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We sincerely thank the affected individuals and their families for participation. We acknowledge R.H. Lyons for excellent large-scale sequencing. We are grateful to the following physicians for contribution of materials and clinical data from patients: J. Kuehr (Karlsruhe, Germany), B. Polak (University of Rotterdam, The Netherlands), D. Doherty (University of Washington, Seattle) and N. Illum (Odense, Denmark). This research was supported by grants from the US National Institutes of Health to F.H. (DK1069274, DK1068306, DK064614), to A.S. (EY07961 and EY07003), to D.S.W. (EY13408) and to I.D. (DK53093), and by grants to A.S. from the Foundation Fighting Blindness and Research to Prevent Blindness (RPB). F.H. is the Frederick G. L. Huetwell Professor. A.S. is the Harold F. Falls Collegiate Professor and recipient of RPB Senior Scientific Investigator Award. M.R.L. holds Michael Smith Foundation for Health Research (MSFHR) and Canadian Institutes of Health Research (CIHR) scholar awards. The work was further supported by the German Federal Ministry of Science and Education through the National Genome Research Network (G.N., C.B., H.C.H. and P.N.); by grants from the German Research Foundation (A.K.); by the National Science Foundation of China (X.Z., grant numbers 30330330 and 30421005); by the March of Dimes and CIHR (grant CBM134736) (M.R.L.); by a grant from the Michigan Economic Development Corporation, Life Sciences Corridor, to D.G. (MEDC38) and a Vision Research Pre-doctoral Training Grant (B.F.); by a grant from the N.K.F. (N004727) (J.F.O.); by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) to T.K. (17018018) and to M.T. (16370075) and by a grant from Japan Space Forum to M.T. (h160179). We thank D. Slusarski for providing maternal pipetail mutant embryos.

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Correspondence to Friedhelm Hildebrandt.

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Supplementary information

Supplementary Fig. 1

Total genome search for linkage by homozygosity mapping for an NPHP/SLSN/JBTS locus in three consanguineous Turkish kindred with two affected children each. (PDF 124 kb)

Supplementary Fig. 2

Alignment of predicted human NPHP6/CEP290 exon structure and EST clones. (PDF 70 kb)

Supplementary Fig. 3

Predicted protein domains and motifs of human NPHP6. (PDF 46 kb)

Supplementary Fig. 4

Characterization of monoclonal antibody to NPHP6 3G4 in HEK293 cells. (PDF 79 kb)

Supplementary Fig. 5

NPHP6 localizes to the centrosome during interphase in COS7 and IMCD3 cells. (PDF 107 kb)

Supplementary Fig. 6

NPHP6 localizes to the centrosome during interphase independent of dynein function. (PDF 421 kb)

Supplementary Fig. 7

Immunogold labeling of NPHP6 with 3G4 antibody in mouse photoreceptor cells. (PDF 273 kb)

Supplementary Table 1

Exon-flanking oligonucleotide primers for PCR in the human CEP290 gene. (PDF 68 kb)

Supplementary Video 1

Pronephric cilia motility in larvae injected with cep290 morpholino (0.05 mM). Cilia beat rate is equivalent or slightly faster than wild-type controls. High-speed video was acquired at 250 fps and replayed at 15 fps (250 frames total; 1 s in real time). (MOV 8388 kb)

Supplementary Video 2

Pronephric cilia motility in zebrafish control wild-type larva. Cilia beat in a helical pattern at 28 Hz in the lumen of the pronephric duct. High-speed video was acquired at 250 fps and replayed at 15 fps (250 frames total; 1 s in real time). (MOV 6814 kb)

Supplementary Methods (PDF 34 kb)

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Sayer, J., Otto, E., O'Toole, J. et al. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 38, 674–681 (2006).

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