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The Centrosomal Protein Nephrocystin-6 Is Mutated in Joubert Syndrome and Activates Transcription Factor ATF4

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The Centrosomal Protein Nephrocystin-6 Is Mutated in Joubert Syndrome and Activates Transcription Factor ATF4 LETTERS The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4 John A Sayer1,2,22, Edgar A Otto1,22, John F O’Toole1, Gudrun Nurnberg3,4, Michael A Kennedy5, Christian Becker3,4, Hans Christian Hennies3,20, Juliana Helou1, Massimo Attanasio1, Blake V Fausett6, Boris Utsch1, Hemant Khanna7, Yan Liu8, Iain Drummond8, Isao Kawakami9, Takehiro Kusakabe9, Motoyuki Tsuda9,LiMa10, Hwankyu Lee11, Ronald G Larson11, Susan J Allen1, Christopher J Wilkinson12, Erich A Nigg12, Chengchao Shou13, Concepcion Lillo14, David S Williams14, Bernd Hoppe15, Markus J Kemper16, Thomas Neuhaus16, Melissa A Parisi17, Ian A Glass17, Marianne Petry18, Andreas Kispert18, Joachim Gloy19, Athina Ganner19, Gerd Walz19, Xueliang Zhu10, Daniel Goldman6, http://www.nature.com/naturegenetics Peter Nurnberg3,20, Anand Swaroop7,21, Michel R Leroux5 & Friedhelm Hildebrandt1,21 The molecular basis of nephronophthisis1, the most frequent adults1. In Senior-Loken syndrome (SLSN) NPHP is associated with genetic cause of renal failure in children and young adults, and retinal degeneration. In Joubert syndrome (JBTS) NPHP is combined its association with retinal degeneration and cerebellar vermis with retinal degeneration, cerebellar vermis aplasia, and mental aplasia in Joubert syndrome2 are poorly understood. Using retardation2. Identification of five genes mutated in NPHP3–7 has positional cloning, we here identify mutations in the gene implicated primary cilia4,5,8,basalbodies7 and mechanisms of planar CEP290 as causing nephronophthisis. It encodes a protein with cell polarity9,10 in the pathogenesis of renal cystic disease11. However, several domains also present in CENPF, a protein involved in it has remained unclear how this pathogenesis is mediated by down- Nature Publishing Group Group Nature Publishing chromosome segregation. CEP290 (also known as NPHP6) stream transcriptional events. In a worldwide cohort of 435 unrelated 6 interacts with and modulates the activity of ATF4, a trans- individuals with NPHP and isolated kidney involvement, 92 indivi- 200 cription factor implicated in cAMP-dependent renal cyst duals with SLSN and 90 individuals with JBTS, recessive mutations of © formation. NPHP6 is found at centrosomes and in the nucleus six known genes (NPHP1, NPHP2, NPHP3, NPHP4, IQCB1 (also of renal epithelial cells in a cell cycle–dependent manner and in known as NPHP5), and AHI1) were detected only in 35% of purely connecting cilia of photoreceptors. Abrogation of its function in renal NPHP cases, in 21% of SLSN cases7, and in 1% of JBTS cases12. zebrafish recapitulates the renal, retinal and cerebellar pheno- To identify further causative genes for NPHP, we performed a whole- types of Joubert syndrome. Our findings help establish the link genome search for linkage by homozygosity mapping using the 10K between centrosome function, tissue architecture and trans- Affymetrix SNP array. criptional control in the pathogenesis of cystic kidney disease, We analyzed 25 consanguineous kindreds with NPHP, SLSN, or retinal degeneration, and central nervous system development. JBTS, ascertained worldwide, each of which had two affected indivi- duals and was negative for mutations in known NPHP genes. Three Nephronophthisis (NPHP), a cystic kidney disease, is the most kindreds showed an overlap of nonparametric lod score (NPL) peaks frequent genetic cause of chronic renal failure in children and young on chromosome 12q that indicated potential homozygosity by 1Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA. 2Institute of Human Genetics, School of Clinical Medical Sciences, University of Newcastle upon Tyne, NE1 3BZ, UK. 3Cologne Center for Genomics, University of Cologne, Cologne, Germany. 4RZPD Deutsches Ressourcenzentrum fuer Genomforschung GmbH, Berlin, Germany. 5Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada. 6Molecular and Behavioral Neuroscience, Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. 7Department of Ophthalmology, University of Michigan, Ann Arbor, Michigan 48109, USA. 8Harvard Medical School and Renal Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. 9Department of Life Science, Graduate School of Life Science, University of Hyogo, Hyogo 678-1297, Japan. 10Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Shanghai 200031, China. 11Departments of Biomedical Engineering and Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA. 12Max-Planck Institute for Biochemistry, Department of Cell Biology, D-82152 Martinsried, Germany. 13Department of Biochemistry and Molecular Biology, Peking University School of Oncology, Beijing Institute for Cancer Research, Beijing 100036 PRC, China. 14Departments of Pharmacology and Neurosciences, School of Medicine, University of California at San Diego, La Jolla, California 92093-9012, USA. 15Department of Pediatrics, University of Cologne, Cologne, Germany. 16Department of Pediatrics, University of Zurich, Zurich, Switzerland. 17Department of Pediatrics, University of Washington, Seattle, Washington 98105, USA. 18Institute for Molecular Biology, Medizinische Hochschule Hannover, D-30625 Hannover, Germany. 19University of Freiburg, Freiburg, Germany. 20Institute for Genetics, University of Cologne, Cologne, Germany. 21Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA. 22These authors contributed equally to this work. Correspondence should be addressed to F.H. ([email protected]). Received 19 December 2005; accepted 21 March 2006; published online 7 May 2006; doi:10.1038/ng1786 674 VOLUME 38 [ NUMBER 6 [ JUNE 2006 NATURE GENETICS LETTERS Figure 1 Positional cloning of the CEP290 gene F700 F944 a as mutated in NPHP6/SLSN6/JBTS6. l:1l:2 l:1 l:2 (a) Haplotype analysis in two consanguineous kindreds. Microsatellite and SNP markers on ll:3ll:1ll:2ll:4 ll:3 ll:1 ll:2 ll:4 chromosome 12q are shown at left (top to bottom, centromere to q-terminal). Boxes with solid lines indicate the extent of homozygosity by lll:3 lll:1 lll:2 lll:1 lll:2 D12S1660 219 221 221 213 217 227 215 215 descent. Haplotype sharing occurs among both D12S1708 186 184 186 182 186184 186 184 12_JS2 217 212 217 223 212 217 212 212 families within a 1.5-Mb interval on chromosome D12S2076 214 208 214 214 214 208 214 214 SNP_A-1517043 2211 2 222 12q21.32-q21.33 (box with dotted line). This D12S1289 287273 287 287 287 279 287 287 D12S1719 239251 239 251 247 249 247 237 defines a critical interval for a putative NPHP6/ SNP_A-1514136 11 1 1 2 221 D12S853 138126 138 134 134 134 134 134 SLSN6/JBTS6 locus under the hypothesis of SNP_A1518307 11 1 1 1 211 12_JS15 312 312 312 312 312 280 312 312 SNP_A1513321 1 111 1 111 haplotype sharing by descent from a postulated 12_JS17 239 243 239 239 239 239 239 239 SNP_A-1507793 2 222 2 222 ancestor common to F700 and F944. Circles 12_JS41 273 273 273 265 273 265273 261 12_JS43 204 202 204 204 199 203 199 195 represent females; squares represent males; filled D12S1678 128 128 128 128 124 128 124 126 SNP_A-1509732 2 221 221 2 symbols denote the presence of JBTS. (b)The SNP_A-1517251 11 1 1 21 11 SNP_A-151621 2 1 11 1111 NPHP6 critical genetic region, as annotated by GenomeBrowser (UCSC May 2004 freeze), Position extends over a 1.5-Mb interval between flanking (Mb) lV:4 lV:6 lV:1 lV:1 D12S1660 219 221219 221 227 215217 215 markers D12S853 and 12_JS43 (underlined). D12S1708 186 186 186 186 184186 186 186 12_JS2 83.6 217 217 217 217 217 212 212 212 Arrows indicate transcriptional direction of all ten D12S2076 214 214 214 214 214 214 214 214 SNP_A-1517043 22 22 22 22 positional candidate genes. Mutations were D12S1289 287 287 287 287 287 287 287 287 D12S1719 239 239 239 239 247 247 247 247 detected in the partially annotated gene CEP290, SNP_A1514136 1 1 1 1 22 22 D12S853 86.3 138 138 138 138 134 134 134 134 SNP_A1518307 11 11 11 11 which was found to be part of a larger gene 12_JS15 312 312 312 312 312 312 312 312 SNP_A1513321 1 1 1 1 1 1 1 1 (including Q9H8I0 and additional exons). This re- 12_JS17 239 239 239 239 239 239 239 239 SNP_A-1507793 22 22 22 22 annotated gene is now termed CEP290 (alias http://www.nature.com/naturegenetics 12_JS41 273 273 273 273 273 273 273 273 12_JS43 87.8 204 204 204 204 199 199 199 199 NPHP6). (c)TheCEP290 gene measures 93.2 D12S1678 128 128 128 128 124 124 124 124 SNP_A-1509732 104.6 2 222 21 21 kb and extends over 55 exons (vertical hatches). SNP_A-1517251 1 1 1 1 21 21 SNP_A-1510621 21 21 1 1 1 1 (d) Exon structure of human CEP290 cDNA. Exon size, which ranged from 21 bp to 465 bp, is b D12S853 12_JS15 12_JS17 12 JS43 D12S1678 86.3 86.6 86.7 87.8 88.6 Mb averaged graphically. (e) Representations of BC067894 FLJ35821 SMILE DKFZp434N2030 CR74922 putative protein motifs shown in relation to the BX648026 KITLG position of the exons encoding them. Lines and CEP290 Q9H810 AK127865 c NPHP6 arrows indicate relative positions of the mutations detected. Protein domains are numbered and 93.2 kb d ATG 300 bp TAA marked as follows: CC, coiled-coil domain; TM, 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 tropomyosin homology domain; KID, RepA/Rep+ e protein KID; NLS_BP, bipartite nuclear Nature Publishing Group Group Nature Publishing CC l CC ll CC lll CC lV CC V CC Vl CC Vll TM l TM ll TM lll KID l KID ll CC lX CC X CC Xl KID lll KID lV KID V KID Vl CC Xll CC Xlll CC Vlll NLS_BP P-LOOP 6 SMC homology localization signal; P-loop, ATP/GTP-binding site 290 kDa, 2479 amino acid residues motif A (P-loop).
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