DOCSLIB.ORG

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

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

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).
Recommended publications
  • GENETIC STUDY of RENAL DISEASES (Nephroref Global®) by MASSIVE SEQUENCING (NGS)

    GENETIC STUDY of RENAL DISEASES (Nephroref Global®) by MASSIVE SEQUENCING (NGS)

    Pablo Iglesias, 57 – Polígono Gran Via Sur 08908 L'Hospitalet de Llobregat (Barcelona) Tel. 932 593 700 – Fax. 932 845 000 GENETIC STUDY OF RENAL DISEASES (NephroRef Global®) BY MASSIVE SEQUENCING (NGS) Request No.: 000 Client: - Analysis code: 55580 Patient Name: xxx Date of Birth: N/A Patient Ref.: xxx Gender: Female Sample Type: Blood EDTA Sample Arrival Date: DD/MM/AAAA Date of Result: DD/MM/AAAA Clinical information: A 9-year-old patient with a nephrotic syndrome without response to corticosteroid therapy. She has nephrotic-range proteinuria with microhematuria, hypoalbuminemia with hypercholesterolemia and normal glomerular filtration. Paternal aunt with cortico-resistant nephrotic syndrome with evolution to end-stage renal failure that required renal transplantation at age 13. RESULT AND INTERPRETATION The presence of a heterozygous likely pathogenic variant has been identified. In addition, the presence of a heterozygous variant of uncertain clinical significance (VUS) has been identified.(See Interpretation and recommendations) The complete list of studied genes is available in Annex 1. (Methodology) The list of reported genes and coverage details is available in Table 1. (Methodology) Gene Variant* Zygosity Inheritance pattern Classification^ NPHS2 NM_014625.3: c.842A>C Heterozygosis Autosomal Recessive Likely Patogénica p.(Glu281Ala) INF2 NM_022489.3: c.67T>A Heterozygosis Autosomal Recessive VUS p.(Ser23Thr) * Nomenclature according to HGVS v15.11 ^ Based on the recommendations of the American College of Medical Genetics and Genomics (ACMG) Physician, technical specialist responsible for Clinical Analysis: Jaime Torrents Pont. The results relate to samples received and analysed. This report may not be reproduced in part without permission. This document is addressed to the addressee and contains confidential information.
  • Leber Congenital Amaurosis Due to CEP290 Mutations – Severe Vision Impairment with a High Unmet Medical Need: a Review Author and Journal Details: Bart P

    Leber Congenital Amaurosis Due to CEP290 Mutations – Severe Vision Impairment with a High Unmet Medical Need: a Review Author and Journal Details: Bart P

    This plain-language summary (or PLS) describes a paper on Leber congenital amaurosis 10 that was published in a medical journal called “Retina”. Title of the paper: Leber congenital amaurosis due to CEP290 mutations – severe vision impairment with a high unmet medical need: a review Author and journal details: Bart P. Leroy, David G. Birch, Jacque L. Duncan, Byron L. Lam, Robert K. Koenekoop, Fernanda B. O. Porto, Stephen R. Russel, Aniz Girach. Retina 2021;doi:10.1097/IAE.0000000000003133. Online ahead of print. What does this paper report on? • The authors of this paper reviewed what scientists know about the genetic eye disease called Leber congenital amaurosis 10 (also known as LCA10). They looked at the scientific articles on this subject that have been published in high-quality medical journals Why was this research needed? • Tying together separate pieces of scientific evidence about a disease can help us to understand the disease better. It also helps identify where there may be areas of care for people with the disease that need to be improved. We call these gaps “unmet medical needs” • Bringing evidence together in this way is especially important for rare diseases as it improves awareness among healthcare professionals of the needs of people living with the disease The authors of the paper are expert eye doctors working at specialist centers in Belgium, Brazil, Canada, and the USA; one of the authors is an employee of ProQR Therapeutics. This PLS has been developed in collaboration with Bart Leroy (an author on the original paper), Francesca Diodati and Matthew Carr, with medical writing assistance provided by ApotheCom.
  • Ciliopathies Gene Panel

    Ciliopathies Gene Panel

    Ciliopathies Gene Panel Contact details Introduction Regional Genetics Service The ciliopathies are a heterogeneous group of conditions with considerable phenotypic overlap. Levels 4-6, Barclay House These inherited diseases are caused by defects in cilia; hair-like projections present on most 37 Queen Square cells, with roles in key human developmental processes via their motility and signalling functions. Ciliopathies are often lethal and multiple organ systems are affected. Ciliopathies are London, WC1N 3BH united in being genetically heterogeneous conditions and the different subtypes can share T +44 (0) 20 7762 6888 many clinical features, predominantly cystic kidney disease, but also retinal, respiratory, F +44 (0) 20 7813 8578 skeletal, hepatic and neurological defects in addition to metabolic defects, laterality defects and polydactyly. Their clinical variability can make ciliopathies hard to recognise, reflecting the ubiquity of cilia. Gene panels currently offer the best solution to tackling analysis of genetically Samples required heterogeneous conditions such as the ciliopathies. Ciliopathies affect approximately 1:2,000 5ml venous blood in plastic EDTA births. bottles (>1ml from neonates) Ciliopathies are generally inherited in an autosomal recessive manner, with some autosomal Prenatal testing must be arranged dominant and X-linked exceptions. in advance, through a Clinical Genetics department if possible. Referrals Amniotic fluid or CV samples Patients presenting with a ciliopathy; due to the phenotypic variability this could be a diverse set should be sent to Cytogenetics for of features. For guidance contact the laboratory or Dr Hannah Mitchison dissecting and culturing, with ([email protected]) / Prof Phil Beales ([email protected]) instructions to forward the sample to the Regional Molecular Genetics Referrals will be accepted from clinical geneticists and consultants in nephrology, metabolic, laboratory for analysis respiratory and retinal diseases.
  • Evidence of Oligogenic Inheritance in Nephronophthisis

    Evidence of Oligogenic Inheritance in Nephronophthisis

    JASN Express. Published on September 12, 2007 as doi: 10.1681/ASN.2007020243 CLINICAL RESEARCH www.jasn.org Evidence of Oligogenic Inheritance in Nephronophthisis Julia Hoefele,*† Matthias T.F. Wolf,* John F. O’Toole,* Edgar A. Otto,* Ulla Schultheiss,* Georges Deˆschenes,‡ Massimo Attanasio,* Boris Utsch,* Corinne Antignac,§ and ʈ Friedhelm Hildebrandt* ʈ Departments of *Pediatrics and Human Genetics, University of Michigan, Ann Arbor, Michigan; †Department of Pediatrics, University Children’s Hospital, University of Munich, Munich, Germany; and ‡Hoˆpital Robert Debre´, Pediatric Nephrology, AP-HP, and §INSERM, U574, Universite´ Paris Descartes, Faculte de Me´dicine Rene´ Descartes, and Hoˆpital Necker-Enfants Malades, AP-HP, Department of Genetics, Paris, France ABSTRACT Nephronophthisis is a recessive cystic renal disease that leads to end-stage renal failure in the first two decades of life. Twenty-five percent of nephronophthisis cases are caused by large homozygous deletions of NPHP1, but six genes responsible for nephronophthisis have been identified. Because oligogenic inheritance has been described for the related Bardet-Biedl syndrome, we evaluated whether mutations in more than one gene may also be detected in cases of nephronophthisis. Because the nephrocystins 1 to 4 are known to interact, we examined patients with nephronophthisis from 94 different families and sequenced all exons of the NPHP1, NPHP2, NPHP3, and NPHP4 genes. In our previous studies involving 44 families, we detected two mutations in one of the NPHP1–4 genes. Here, we detected in six families two mutations in either NPHP1, NPHP3, or NPHP4, and identified a third mutation in one of the other NPHP genes. Furthermore, we found possible digenic disease by detecting one individual who carried one mutation in NPHP2 and a second mutation in NPHP3.
  • Intrafamilial Variability and Clinical Heterogeneity in Two Siblings With

    Intrafamilial Variability and Clinical Heterogeneity in Two Siblings With

    r Biomar ula ke c rs le o & M D f i a o g l Journal of Molecular Biomarkers n a o n Nabhan, et al., J Mol Biomark Diagn 2015, 6:2 r s i u s o J DOI: 10.4172/2155-9929.1000217 ISSN: 2155-9929 & Diagnosis Case Report Open Access Intrafamilial Variability and Clinical Heterogeneity in Two Siblings with NPHP4 loss of Function Mutations Marwa M Nabhan1,2, Susann Brenzinger3, Sahar N Saleem4, Edgar A Otto3, Friedhelm Hildebrandt3,5 and Neveen A Soliman1,2* 1Center of Pediatric Nephrology and Transplantation, Department of Pediatrics, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt 2Egyptian Group for Orphan Renal Diseases (EGORD), Cairo, Egypt 3Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 4Radiology Department, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt 5Howard Hughes Medical Institute, Chevy Chase, USA *Corresponding author: Neveen A Soliman, Center of Pediatric Nephrology & Transplantation, Department of Pediatrics, Kasr Al Aini School of Medicine, Cairo University, Cairo, Egypt, Tel: 0201062132300; Fax: 020223630039; E-mail: [email protected] Rec date: Nov 27, 2014; Acc date: Jan 26, 2015; Pub date: Jan 28, 2015 Copyright: © 2015 Nabhan MM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Joubert syndrome–related disorders (JSRDs) are a group of clinically and genetically pleiotropic conditions that share a midbrain-hindbrain malformation, the pathognomonic molar tooth sign (MTS) visible on brain imaging, with variable involvement of other organs and systems mainly the eyes and the kidneys.
  • Senior-Loken Syndrome: a Novel NPHP5 Gene Mutation in a Family from Kuwait

    Senior-Loken Syndrome: a Novel NPHP5 Gene Mutation in a Family from Kuwait

    The Egyptian Journal of Medical Human Genetics (2014) 15, 203–207 Ain Shams University The Egyptian Journal of Medical Human Genetics www.ejmhg.eg.net www.sciencedirect.com CASE REPORT Senior-Loken syndrome: A novel NPHP5 gene mutation in a family from Kuwait Makia J Marafie a,*, Fahd Al-Mulla b a Kuwait Medical Genetics Centre, Maternity Hospital, Sabah Medical Area, P.O. Box 5833, Safat 13059, Kuwait b Department of Pathology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait Received 30 November 2013; accepted 15 December 2013 Available online 8 January 2014 KEYWORDS Abstract Background: Rare autosomal recessive disorders of variable severity are segregating in Arab; many highly consanguineous families from the Arab population. One of these deleterious diseases Ciliopathy; is Senior-Loken syndrome, a hereditary heterogeneous multiorgan disorder, which combines neph- Consanguinity; ronophthisis with retinal dystrophy, leading to blindness and eventually end stage renal failure. This Nephronophthisis; disorder has been reported in many cases worldwide, including two unrelated families from Arabian Senior-Loken syndrome; Gulf countries, which share the gene pool with Kuwait. Premarital counselling Case report: Here, we are reporting two children from an Arab family with a novel frameshift mutation found in IQCB1/NPHP5 gene; c.1241-1242delTC, predicted to cause protein termination p.Leu414HisfsStop4, and describing the associated clinical features. Conclusion: Identification of this pathogenic mutation helped in confirmation of the clinical diagnosis and in providing a proper pre-marital genetic counselling and testing for a couple embarking on marriage from this highly consanguineous high-risk family. Ó 2013 Production and hosting by Elsevier B.V.
  • Clinical Utility Gene Card For: Joubert Syndrome - Update 2013

    Clinical Utility Gene Card For: Joubert Syndrome - Update 2013

    European Journal of Human Genetics (2013) 21, doi:10.1038/ejhg.2013.10 & 2013 Macmillan Publishers Limited All rights reserved 1018-4813/13 www.nature.com/ejhg CLINICAL UTILITY GENE CARD UPDATE Clinical utility gene card for: Joubert syndrome - update 2013 Enza Maria Valente*,1,2, Francesco Brancati1, Eugen Boltshauser3 and Bruno Dallapiccola4 European Journal of Human Genetics (2013) 21, doi:10.1038/ejhg.2013.10; published online 13 February 2013 Update to: European Journal of Human Genetics (2011) 19, doi:10.1038/ejhg.2011.49; published online 30 March 2011 1. DISEASE CHARACTERISTICS 1.6 Analytical methods 1.1 Name of the disease (synonyms) Direct sequencing of coding genomic regions and splice site junctions; Joubert syndrome (JS); Joubert-Boltshauser syndrome; Joubert syn- multiplex microsatellite analysis for detection of NPHP1 homozygous drome-related disorders (JSRD), including cerebellar vermis hypo/ deletion. Possibly, qPCR or targeted array-CGH for detection of aplasia, oligophrenia, congenital ataxia, ocular coloboma, and hepatic genomic rearrangements in other genes. fibrosis (COACH) syndrome; cerebellooculorenal, or cerebello-oculo- renal (COR) syndrome; Dekaban-Arima syndrome; Va´radi-Papp 1.7 Analytical validation syndrome or Orofaciodigital type VI (OFDVI) syndrome; Malta Direct sequencing of both DNA strands; verification of sequence and syndrome. qPCR results in an independent experiment. 1.2 OMIM# of the disease 1.8 Estimated frequency of the disease 213300, 243910, 216360, 277170. (incidence at birth-‘birth prevalence’-or population prevalence) No good population-based data on JSRD prevalence have been published. A likely underestimated frequency between 1/80 000 and 1.3 Name of the analysed genes or DNA/chromosome segments 1/100 000 live births is based on unpublished data.
  • Research Article Mouse Model Resources for Vision Research

    Research Article Mouse Model Resources for Vision Research

    Hindawi Publishing Corporation Journal of Ophthalmology Volume 2011, Article ID 391384, 12 pages doi:10.1155/2011/391384 Research Article Mouse Model Resources for Vision Research Jungyeon Won, Lan Ying Shi, Wanda Hicks, Jieping Wang, Ronald Hurd, Jurgen¨ K. Naggert, Bo Chang, and Patsy M. Nishina The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA Correspondence should be addressed to Patsy M. Nishina, [email protected] Received 1 July 2010; Accepted 21 September 2010 Academic Editor: Radha Ayyagari Copyright © 2011 Jungyeon Won et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The need for mouse models, with their well-developed genetics and similarity to human physiology and anatomy, is clear and their central role in furthering our understanding of human disease is readily apparent in the literature. Mice carrying mutations that alter developmental pathways or cellular function provide model systems for analyzing defects in comparable human disorders and for testing therapeutic strategies. Mutant mice also provide reproducible, experimental systems for elucidating pathways of normal development and function. Two programs, the Eye Mutant Resource and the Translational Vision Research Models, focused on providing such models to the vision research community are described herein. Over 100 mutant lines from the Eye Mutant Resource and 60 mutant lines from the Translational Vision Research Models have been developed. The ocular diseases of the mutant lines include a wide range of phenotypes, including cataracts, retinal dysplasia and degeneration, and abnormal blood vessel formation.
  • Ciliary Genes Arl13b, Ahi1 and Cc2d2a Differentially Modify Expression of Visual Acuity

    Ciliary Genes Arl13b, Ahi1 and Cc2d2a Differentially Modify Expression of Visual Acuity

    bioRxiv preprint doi: https://doi.org/10.1101/569822; this version posted March 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Ciliary Genes arl13b, ahi1 and cc2d2a Differentially Modify Expression of Visual Acuity 2 Phenotypes but do not Enhance Retinal Degeneration due to Mutation of cep290 in Zebrafish 3 4 Short title: Retinal degeneration in cep290 mutant zebrafish 5 6 7 Emma M. Lessieur1,2,4, Ping Song1,4, Gabrielle C. Nivar1, 8 Ellen M. Piccillo1, Joseph Fogerty1, Richard Rozic3, and Brian D. Perkins1,2 9 10 1Department of Ophthalmic Research, Cole Eye Institute, 11 Cleveland Clinic, Cleveland, OH 44195 United States 12 2Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, 13 Case Western Reserve University, Cleveland, OH 44195 United States 14 3Department of Biomedical Engineering, Lerner Research Institute, 15 Cleveland Clinic, Cleveland, OH 44195 United States 16 17 4These authors contributed equally to this work 18 Correspondence to: 19 Brian D. Perkins, Ph.D. 20 Department of Ophthalmic Research 21 Cleveland Clinic 22 9500 Euclid Ave 23 Building i3-156 24 Cleveland, OH 44195, USA 25 (Ph) 216-444-9683 26 (Fax) 216-445-3670 27 [email protected] 28 29 1 bioRxiv preprint doi: https://doi.org/10.1101/569822; this version posted March 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
  • Distinguishing the Four Genetic Causes of Jouberts Syndrome-Related

    Distinguishing the Four Genetic Causes of Jouberts Syndrome-Related

    Mutations in the CEP290 gene, encoding a centrosomal protein, cause pleiotropic forms of Joubert Syndrome Enza Maria Valente,1* Jennifer L. Silhavy,2* Francesco Brancati,1,3 Giuseppe Barrano,1,4 Suguna Rani Krishnaswami,2 Marco Castori,1,4 Madeline A. Lancaster, 2 Eugen Boltshauser,5 Loredana Boccone,6 Lihadh Al-Gazali,7 Elisa Fazzi,8 Sabrina Signorini,8 Carrie M. Louie, 2 Emanuele Bellacchio,1 the International JSRD Study Group, Enrico Bertini,9 Bruno Dallapiccola,1,4 Joseph G. Gleeson.2 1IRCCS CSS, Mendel Institute, viale Regina Margherita 261, 00198 Rome, Italy, tel. +39 (06) 4416 0503 2Laboratory of Neurogenetics, Department of Neurosciences, University of California, San Diego, Leichtag 332, 9500 Gilman Drive, La Jolla, CA 92093-0691, USA, tel. +1 (858) 822 3535 3Department of Biological Sciences, G. D’Annunzio University, Via dei Vestini 31, 66013 Chieti, Italy, tel. +39 (0871) 3554137 4Department of Experimental Medicine and Pathology, La Sapienza University, viale Regina Elena 324, 00187 Rome, Italy, tel. +39 (06) 4416 0501 5Department of Neurology, Children's University Hospital, Steinwiesstrasse 75, 8032 Zurich, Switzerland, tel. +41 (1) 266 7330 6Ospedale Microcitemico, Cagliari, Italy, tel. +39 (070) 6095666 7Department of Pediatrics, Faculty of Medicine and Health Sciences, United Emirates University, PO Box 17666, Al Ain, United Arab Emirates, tel. +971 (3) 703 9415 and +971 (3) 767 2022 8Department of Child Neurology and Psychiatry, IRCCS "C. Mondino Foundation", University of Pavia, Italy, tel. +39 (0382) 380 280 9Molecular Medicine Unit, Department of Laboratory Medicine, Bambino Gesu' Hospital IRCCS, Piazza S. Onofrio, 4, 00165 Rome, Italy, tel. +39 (06) 6859 2105 *these two authors contributed equally to this work.
  • Information Sheet on Ciliopathy Testing

    Information Sheet on Ciliopathy Testing

    The University of Chicago Genetic Services Laboratories 5841 S. Maryland Ave., Rm. G701, MC 0077, Chicago, Illinois 60637 [email protected] dnatesting.uchicago.edu CLIA #: 14D0917593 CAP #: 18827-49 Next Generation Sequencing Panel for Joubert and Meckel Gruber Syndrome Joubert syndrome Joubert syndrome (JBTS) is characterized by hypotonia, oculomotor apraxia, nystagmus, and intellectual disability. In these patients, brain MRI reveals the pathognomonic “molar tooth sign” (MTS) with absent or hypoplastic cerebellar vermis, deepened interpenduncular fossa, and elongated superior cerebellar peduncles. The term Joubert syndrome and related disorders (JSRD) is used to describe individuals who, in addition to having the core neurological features, also have additional findings including retinal dystrophy, ocular colobomas, kidney disease, liver fibrosis, occipital encephalocele, oral hamartomas, endocrine abnormalities and polydactyly (1). Meckel Gruber syndrome Meckel Gruber syndrome (MKS) is the most common syndromic form of neural tube defect and the classic triad of clinical features is characterized by occipital encephalocele, cystic kidneys and fibrotic changes to the liver. The clinical phenotype has since been broadened to include features such as postaxial polydactyly, skeletal dysplasia, microphthalmia, genital anomalies, cleft lip and palate, and heart defects (2). Our Joubert/Meckel-Gruber Syndrome Panel includes all 26 genes listed below. Our Meckel-Gruber Syndrome Panel includes all 11 genes listed below. (Deletion/duplication analysis is available for most genes; sequencing only is available for starred genes.) Joubert/Meckel-Gruber Syndrome Meckel-Gruber Syndrome AHI1 CSPP1* RPGRIP1L TMEM237 B9D1* TMEM67 ARL13B INPP5E TCTN1 TTC21B B9D2* TMEM216 B9D1* KIF7 TCTN2 CC2D2A TMEM231 B9D2* OFD1 TCTN3 CEP290 C5orf42 MKS1 TMEM67 MKS1 CC2D2A NPHP1 TMEM138 NPHP3* CEP41 NPHP3* TMEM216 RPGRIP1L CEP290 PDE6D* TMEM231 TCTN2 The genes implicated in JSRD and MKS all play roles in the formation or function of sensory cilia.
  • The Novel and Independent Association Between Single-Point SNP of NPHP4 Gene and Renal Function in Non-Diabetic Japanese Population: the Takahata Study

    The Novel and Independent Association Between Single-Point SNP of NPHP4 Gene and Renal Function in Non-Diabetic Japanese Population: the Takahata Study

    Journal of Human Genetics (2010) 55, 791–795 & 2010 The Japan Society of Human Genetics All rights reserved 1434-5161/10 $32.00 www.nature.com/jhg ORIGINAL ARTICLE The novel and independent association between single-point SNP of NPHP4 gene and renal function in non-diabetic Japanese population: the Takahata study Tsuneo Konta1, Satoshi Takasaki1, Kazunobu Ichikawa1, Mitsuru Emi2, Sayumi Toriyama2, Hitoshi Satoh1, Ami Ikeda1, Kazuko Suzuki1, Yusuke Mashima1, Yoko Shibata1, Tetsu Watanabe1, Takeo Kato3, Sumio Kawata4 and Isao Kubota1 Nephronophthisis (NPHP) 4 gene coding nephrocystin-4 is involved in the development of renal tubules and its congenital mutations cause juvenile end-stage renal disease, NPHP. To investigate the association between single-point single-nucleotide polymorphism (SNP) of NPHP4 gene and renal function, we conducted a cross-sectional study in Japanese population. The subjects of this study were non-diabetic general population consisting of 2604 individuals 440 years in Takahata town, Japan. We genotyped 11 SNPs within NPHP4 gene that displayed frequent minor allele frequencies (40.1) in Japanese general population. Among 11 SNPs in NPHP4 gene, only rs1287637 that induces amino acid substitution (A (Gln)/T (Leu)), located in the acceptor site of exon 21, showed a significant association with estimated glomerular filtration rate (eGFR; T/T: 81.3±15.6 (n¼1886), A/T: 82.0±15.5 (n¼652) and A/A: 87.4±21.4 ml minÀ1 per 1.73m2 (n¼66); mean±s.d., P¼0.006). This SNP was not in linkage disequilibrium with the surrounding SNPs. The multivariate analysis adjusted with possible confounders showed that the A/T+T/T genotype of rs1287637 was independently associated with reduced renal function (eGFR o90 ml minÀ1 per 1.73m2; odds ratio (OR) 1.75, 95% confidence interval (CI) 1.05–2.94, P¼0.033).