DOCSLIB.ORG

Mutations in Pycrl Cause Cutis Laxa with Progeroid Features Genetics

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mutations in Pycrl Cause Cutis Laxa with Progeroid Features Genetics nature genetics Mg101 Mutations in PYCRl cause cutis laxa with progeroid features Bruno Reversade1 •33, Nathalie Escande-Beillard Aikaterini Dimopoulou2, Björn Fischer2, Serene C Chng1, Yun Li3, Mohammad Shboul1, Puay-Yoke Tham1, Hülya Kayserilf, Lihadh Al-Gazali5, Monzer Shahwan6, Francesco Brancati7'8, Hane Lee9, Brian D O'Connor9, Mareen Schmidt-von Kegler2' 10, Barry Merriman9, Stanley F Nelson9, Amira Masri11 , Fawaz Deanna Guerra12, Paola Ferrari13, Arti Nanda14, Anna Rajab 15 , David Markie16, Mary Gray16, John Nelson17, Arthur Grix18, Annemarie Sommer19, Ravi Savarirayan20, Andreas R Janecke21 , 22, 23, lal Elisabeth Steichen David Sillence Ingrid HauBer24, e Birgit Budde25, Gudrun Nürnberg25, Peter Nürnberg25, Petra Seemann10,26, Desiree Kunkel26, Giovanna Zamhruno27, Bruno Dallapiccola7, Markus Schuelke28, Stephen Robertson29, Hanan Hamamy6, Ol 32 2 10 26 ·;:: Bernd Lionel Van Maldergem , Stefan Mundlos • • & Uwe Autosomal recessive cutis laxa (ARCL) describes a group findings link mutations in PYCR1 to altered mitochondrial of syndromal disorders that are often associated with a function and progeroid changes in connective tissues. progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation 1- 3• Homozygosity mapping in Wrinkly skin and bone loss are typical features associated with several kindreds with ARCL identified a candidate region aging. In some monogenetic diseases these changes occur prema- e on chromosome 17q25. By high-throughput sequencing of turely, resulting in a progeroid appearance of affected individuals. 1ii the entire candidate region, we detected disease-causing As a clinical feature, wrinkly skin or cutis laxa is used as a z mutations in the gene PYCR1. We found that the gene common denominator of several overlapping syndromal disorders product, an enzyme involved in proline metabolism, localizes including autosomal dominant cutis laxa (MIM123700), autoso- to mitochondria. Altered mitochondrial morphology, mal recessive cutis laxa type I (MIM219100), autosomal recessive membrane potential and increased apoptosis rate upon cutis laxa type II (ARCL2; MIM219200, also called wrinkly skin oxidative stress were evident in from affected syndrome (WSS; MIM2782S0)), de Barsy syndrome (DBS; & individuals. Knockdown of the orthologous genes in Xenopus MIM219150), and gerodermia osteodysplastica (MIM231070)1-4. and led to epidermal hypoplasia and blistering that Diagnosis is often difficult in thesc conditions owing to a broad - was accompanied by a massive increase of apoptosis. Our clinical overlap5•6• of Medical Biology, A*STAR, Singapore, Singapore. 2Institute of Medical Genetics, Charite Universitaetsmedizin Berlin, Germany. 3Center tor Molecular Medicine Cologne, University of Cologne, Cologne, Germany. 4 Medical Genetics Department, lstanbul Medical Faculty, University of lstanbul, Turkey. 5 Department of Paediatrics, Faculty of and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. Center for Endocrinology and Genetics, Amman, Jordan. 70spedale Casa Sollievo della Sofferenza (CSS), San Giovanni Rotanda and lstituto CSS-Mendel, Rome, ltaly. 8centro Studi lnvecchiamento (Ce.S.I.), Department of Biomedical Sciences, Gabriele d'Annunzio University, Chieti, ltaly. 9Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. 10Max Planck lnstitute for Molecular Genetics, Bertin, Germany. 11 Departments of Pediatrics, and Gynecology, Faculty of Medicine, The University of Jordan, Amman, Jordan. 12 Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, ltaly. 13Department of Pediatrics, University of Modena and Reggio Emilia, Modena, ltaly. 14As'ad AI-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait City, Kuwait. 15Genetic Unit, Directorate General of Health Affairs, Ministry of Health, Muscat, Sultanate of Oman. 16Department of Pathology, University of Otago, Dunedin, New Zealand. 17Genetic Services of Western Australia, King Edward Memorial Hospital tor Women, Perth, Australia. 18The Permanente Medical Group, Sacramento, California, USA. 19The Ohio State University College of Medicine and Nationwide Children's Hospital, Molecular and Human Genetics, Columbus, USA. 20university of Melbourne, Murdoch Childrens Research lnstitute, Royal Children's Hospital, and Genetic Health Services Victoria, Parkville, Victoria, 21 Division of Clinical Genetics, lnnsbruck Medical University, lnnsbruck, Austria. 22 Kiinik fuer Kinder- und Jugendheilkunde, Universitaet lnnsbruck, lnnsbruck. Austria. 23Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia. 24Universitaets-Hautklinik Heidelberg, Heidelberg, Germany. 25Cologne Center tor Genomics, Universitat zu Köln, Germany. 26Berlin-Brandenburg Center for Regenerative Therapies, Charite Universitaetsmedizin Berlin, Germany. 27 Laboratory of Molecular and Celi Biology, lstituto Dermopatico dell'lmmacolata-lstituto di Ricovero e Cura a Carattere Rome, ltaly. 28Department of Neuropediatrics and NeuroCure Clinical Research Center, Charite Universitaetsmedizin Beri in, Germany. 29Department of Paediatrics and Child Health, University of Otago, Dunedin, New Zealand. 3°Cologne Excellence Ciuster on Cellular Stress Responses Aging-Associated (CECAD), University of Cologne, Cologne, Germany. 31 institute of Human Genetics, University of Cologne, Cologne, Germany. 32Centre de Genetique Humaine, Centre Hospitalier Universitaire du iman, Universite de Liege, Liege, Belgi um. 33These authors contributed equally to !his work. Correspondence should be addressed to B.R.([email protected]) or S.M.([email protected]). Received 15 April; accepted 3 June; published online 2 August 2D09; doi:10.1038/ng.413 1016 VOLUME 41 1 NUMBER 9 1 SEPTEMBER 2009 NATURE GENETICS Table 1 Phenotypic characteristics of investigated subjects with ARCL Phenotypic findings Mutations L.ax, Abnormal Literature Na. aff. wrinkly H ip Osteo- corpus Mental Athetoid in iti al ref. on Family Origin ind. IUGR skin dislocation Hernias penia callosum retardation movernents Cataract diagnosis Status cDNA Consequence Exor phenotype J.I. lraq + ++ + + wss Horn 13B+IG>A ND 2 T.P. Palestine + + ND + + + wss Horn 616G>T G206W 5 7 S.P. Palestine 3 + ++ + + +/- +/- GO or WSS Hom 617 _633+6del ND 5 5 I.K. Kuwait 2 + ++ ++ ++ ++ + GO or WSS Hom 797G>A R266Q + splicing 6 6 F.S. Kuwait + + ++ ++ ++ + GO or WSS Hom 797G>A R266Q + splic,ng 6 6 S.J. Jordan 5 + ++ + ND + + wss Horn 797+2_797 K215_D319del 6 +5del D.I. ltaly + ++ ++ ++ ND + GO Het lldelG G4fsX50 Het 355C>G Rl 19G 4 s.o. Oman ++ + + GO Het 356G>A Rl19H 4 Het 566C> T A189V 5 G.O Oman 3 ND ++ + ND + GO Hom 356G>A Rl19H 4 H.B. Bahrain 2 + ++ ++ + ND + GO Hom 535G>A A179T 4 M.A. Austria 1 + + ++ + ++ ND + GO Hom 540+1G>A ND 4 M.Q Qalar ND ++ ++ + ++ ND + GO Hom 616G>A G206R 5 H.U. United States + + G) + + GO Hom 633+!G>C ND 5 8 NA Australia + ++ + + ND ND + GD Het 633+1G>C ND 5 G) Het 797+1G> T ND 6 A.S. Syria + + + + + + GO Hom 797+2_797+5del K215_D319del 6 5 e D.T Turkey + ++ ND ND +/- DBS Hom 355C>G Rll9G 4 M.F. ltaly + ++ ND ++ ND ND + DBS Het 355C>G Rl19G 4 3 E01 ·;:: DBS Het 356G>A Rt I9H 4 S.T. Turkey 2 + + ND + + DBS Hom 540+1G>A ND 6 E.U. Un ited States 1 + ++ + ++ ND + + + DBS Hom 752G>A R251H 6 J.A. Australia (,) 3 + ++ ND ND ++ + DBS Hom 769G>A A257T 6 9 K.l Turkey .5 + + ND + + DBS Hom 797G>A R266Q + 6 I.T. Turkey t + + + ND + DBS Hom 797+2_797+5del K2 l 5_D319del 6 ;: GO, gerodermia osteodysplastica; WSS, wrinkly skin syndrome; DBS, de Barsy syndrome. No. afi. ind., number of affected individuals family; G) IUGR, intrauterine growth retardation; Hom, homozygous; Het, heterozygous. ND, not determined; +/-, mild; average; E +, ++, strong. For hernias: +, unilateral; ++, bilateral. < f Here we describe mutations in PYCRJ associated with a spectrum Both methods identified mutations in PYCRl, the gene encoding the 1ii of disorders characterized by wrinkly skin, osteopenia and progeroid enzyme A1-pyrroline-5-carboxylate reductase 1 (PYCRl). z appearance. The clinical features of the 35 affected individuals from 22 In total, we identified eight missense mutations, one frameshift families included in our study are summarized in Table 1. They mutation, fivc splice-sitc mutations and one 22-bp deletion encom- include congenital skin wrinkling, most pronounced on the dorsum of passing the exon-intron boundary of exon 5 (Table 1 and Supple- hands and teet; generalized connective tissue weakness; finger con- mentary Fig. la). Six of these mutations were recurrent, even tractures; hernias; osteopenia; and a triangular face with a progeroid though the affected individuals did not have a common ethnic & appearance that is due to lax skin and hypoplasia of the jaw often background. Bioinformatic analysis predicted deleterious effects for W resulting in prognathism (Fig. Ia-d), Ultrastructural investigation of ali changes with the exception of the heterozygous Al89V, for the skin showed rarefaction and fragmentation of elastic fibers similar which we cannot rule aut the possibility that it is a rare variant to changes described in ARCL2 (Fig. le-h). No glycosylation abnorm- (Supplementary Fig. Ih). alities were detected by standard diagnostics (data not shown). A As skin was the most severely affected organ, we isolated skin variable degree of mental retardation was observed in all cases but one. fibroblasts from probands and their unaffected siblings to In many subjects,
Load more

Recommended publications
  • Daniel Bernstein, MD Associate Dean for Curriculum and Scholarship Stanford University School of Medicine Alfred Woodley Salter and Mabel G
    RESEARCHER PROFILES Daniel Bernstein, MD Associate Dean for Curriculum and Scholarship Stanford University School of Medicine Alfred Woodley Salter and Mabel G. Salter Endowed Professor of Pediatrics (Cardiology) Stanford University Former Division Chief, Pediatric Cardiology Former Director, Children’s Heart Center, Lucile Packard Children’s Hospital at Stanford EMAIL [email protected] PROFILE med.stanford.edu/profiles/Daniel-Bernstein LAB murinecvcore.stanford.edu CURRENT RESEARCH EDUCATION/TRAINING Our recent work has focused on the mechanism by which mutations in sarcomeric proteins such MD New York University as myosin lead to the clinical phenotypes of hypertrophic cardiomyopathy (HCM). Utilizing human induced pluripotent stem cell-derived cardiomyocytes, with mutations induced by CRISPR/Cas9 PEDIATRICS RESIDENCY Montefiore Medical Center gene editing, we are undertaking a multi-scale approach ranging from structural and function studies on the single myosin molecule, to the individual myofibril, to whole cells and to microengineered MEDICAL EDUCATION FELLOWSHIP Albert Einstein College of Medicine tissues. To better understand cardiomyocyte mechano-transduction, we are applying FRET sensors in critical sarcomeric and junctional proteins. We are also studying a large biobank of myocardial PEDIATRIC CARDIOLOGY FELLOWSHIP UCSF samples from patients with HCM, combining transcriptomics and metabolomics with measurements of mitochondrial function to determine the degree to which HCM is a disease of altered cardiac BOARD CERTIFICATION Pediatrics, ABP energetics. These studies will allow us to correlate findings from hiPSC-CMs with actual patient samples. Another focus of our lab has been on the molecular mechanisms of RV hypertrophy Pediatric Cardiology, ABP and its transition to RV failure, and how this differs from LV failure.
    [Show full text]
  • DPP9 Is an Endogenous and Direct Inhibitor of the NLRP1 Inflammasome That Guards Against Human Auto-Inflammatory Diseases
    bioRxiv preprint doi: https://doi.org/10.1101/260919; this version posted February 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. DPP9 is an endogenous and direct inhibitor of the NLRP1 inflammasome that guards against human auto-inflammatory diseases Franklin L. Zhong1,2,3,*, Kim Robinson2,3, Chrissie Lim1, Cassandra R. Harapas4, Chien- Hsiung Yu4, William Xie2, Radoslaw M. Sobota1, Veonice Bijin Au1, Richard Hopkins1, John E. Connolly1,6,7, Seth Masters4,5 , Bruno Reversade1,2,8,9,10 *, # 1. Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Proteos, Singapore 138673 2. Institute of Medical Biology, A*STAR, 8A Biomedical Grove, Immunos, Singapore 138648 3. Skin Research Institute of Singapore (SRIS), 8A Biomedical Grove, Immunos, Singapore 138648 4. Inflammation division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. 5. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010 Australia 6. Institute of Biomedical Studies, Baylor University, Waco, Texas 76712, USA 7. Department of Microbiology and Immunology, National University of Singapore, 5 Science Drive 2, Singapore 117545 8. Reproductive Biology Laboratory, Obstetrics and Gynaecology, Academic Medical Center (AMC), Meibergdreef 9, 1105 AZ Amsterdam-Zuidoost, Netherlands 9. Department of Paediatrics, National University of Singapore, 1E Kent Ridge Road, Singapore 119228 10. Medical Genetics Department, Koç University School of Medicine, 34010 Istanbul, Turkey * Corresponding authors. F.L.Z., [email protected]; B.R., [email protected] # Lead contact 1 bioRxiv preprint doi: https://doi.org/10.1101/260919; this version posted February 7, 2018.
    [Show full text]
  • Genes in Eyecare Geneseyedoc 3 W.M
    Genes in Eyecare geneseyedoc 3 W.M. Lyle and T.D. Williams 15 Mar 04 This information has been gathered from several sources; however, the principal source is V. A. McKusick’s Mendelian Inheritance in Man on CD-ROM. Baltimore, Johns Hopkins University Press, 1998. Other sources include McKusick’s, Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders. Baltimore. Johns Hopkins University Press 1998 (12th edition). http://www.ncbi.nlm.nih.gov/Omim See also S.P.Daiger, L.S. Sullivan, and B.J.F. Rossiter Ret Net http://www.sph.uth.tmc.edu/Retnet disease.htm/. Also E.I. Traboulsi’s, Genetic Diseases of the Eye, New York, Oxford University Press, 1998. And Genetics in Primary Eyecare and Clinical Medicine by M.R. Seashore and R.S.Wappner, Appleton and Lange 1996. M. Ridley’s book Genome published in 2000 by Perennial provides additional information. Ridley estimates that we have 60,000 to 80,000 genes. See also R.M. Henig’s book The Monk in the Garden: The Lost and Found Genius of Gregor Mendel, published by Houghton Mifflin in 2001 which tells about the Father of Genetics. The 3rd edition of F. H. Roy’s book Ocular Syndromes and Systemic Diseases published by Lippincott Williams & Wilkins in 2002 facilitates differential diagnosis. Additional information is provided in D. Pavan-Langston’s Manual of Ocular Diagnosis and Therapy (5th edition) published by Lippincott Williams & Wilkins in 2002. M.A. Foote wrote Basic Human Genetics for Medical Writers in the AMWA Journal 2002;17:7-17. A compilation such as this might suggest that one gene = one disease.
    [Show full text]
  • Novel Mutations in the Ciliopathy-Associated Gene CPLANE1 (C5orf42) Cause OFD Syndrome Type VI Rather Than Joubert Syndrome
    Accepted Manuscript Novel mutations in the ciliopathy-associated gene CPLANE1 (C5orf42) cause OFD syndrome type VI rather than Joubert syndrome Carine Bonnard, Mohammad Shboul, Seyed Hassan Tonekaboni, Alvin Yu Jin Ng, Sumanty Tohari, Kakaly Ghosh, Angeline Lai, Jiin Ying Lim, Ene Choo Tan, Louise Devisme, Morgane Stichelbout, Adila Alkindi, Nazreen Banu, Zafer Yüksel, Jamal Ghoumid, Nadia Elkhartoufi, Lucile Boutaud, Alessia Micalizzi, Maggie Siewyan Brett, Byrappa Venkatesh, Enza Maria Valente, Tania Attié-Bitach, Bruno Reversade, Ariana Kariminejad PII: S1769-7212(17)30410-X DOI: 10.1016/j.ejmg.2018.03.012 Reference: EJMG 3440 To appear in: European Journal of Medical Genetics Received Date: 30 June 2017 Revised Date: 28 March 2018 Accepted Date: 28 March 2018 Please cite this article as: C. Bonnard, M. Shboul, S.H. Tonekaboni, A.Y.J. Ng, S. Tohari, K. Ghosh, A. Lai, J.Y. Lim, E.C. Tan, L. Devisme, M. Stichelbout, A. Alkindi, N. Banu, Z. Yüksel, J. Ghoumid, N. Elkhartoufi, L. Boutaud, A. Micalizzi, M.S. Brett, B. Venkatesh, E.M. Valente, T. Attié-Bitach, B. Reversade, A. Kariminejad, Novel mutations in the ciliopathy-associated gene CPLANE1 (C5orf42) cause OFD syndrome type VI rather than Joubert syndrome, European Journal of Medical Genetics (2018), doi: 10.1016/j.ejmg.2018.03.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
    [Show full text]
  • Media Release for Immediate Release
    MEDIA RELEASE FOR IMMEDIATE RELEASE 22 May 2018 New genetic findings explain how embryos form arms and legs New discovery revises biologists’ understanding of how limbs and lungs develop in humans. The current understanding of limb and lung development in humans does not capture the full picture of the process, according to research published in Nature last week. This paper describes the importance of novel genes for limb development, and shows how perceived wisdom about the process was incomplete. An international group of clinicians and researchers from Singapore, Turkey, France, Portugal and India, studied five families with either limb malformations, or tetra-amelia syndrome that is characterised by the absence of lungs and all four limbs. They found that mutations in the RSPO2 gene lead to incomplete limb development. Until now, the RSPO proteins were believed to only work with their receptors called LGRs. Together, RSPO and LGRs were thought to allow limb formation by blocking two key enzymes ZNRF3 and RNF43. Or so we thought. The team then studied mice lacking all three LGRs required for RSPO2’s function, and found that contrary to what was expected they still developed limbs and lungs normally. This indicates that RSPO2 does not need LGRs — disproving the established understanding of how this is happening. “Our results establish that even without the LGR receptors, RSPO2, can bind to other molecules and constitute a master switch that governs limb development,” says Dr Emmanuelle Szenker-Ravi, a co-first author of the study based at Agency of Science, Technology and Research’s (A*STAR) Institute of Medical Biology (IMB) in Singapore.
    [Show full text]
  • Neuralization of Dissociated Xenopus Cells Is Mediated by Ras/MAPK Activation
    Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION tive signals that act through Receptor Tyrosine kinases Default neural induction: (RTKs). Growth factors that signal via RTKs, such as neuralization of dissociated Fibroblast Growth Factor (FGF), Insulin-like Growth Factor (IGF), and Hepatocyte Growth Factor (HGF), are Xenopus cells is mediated potent neural inducers in vertebrates (Wilson and Edlund by Ras/MAPK activation 2001; De Robertis and Kuroda 2004; Stern 2004). RTK signaling activates the mitogen-activated protein kinase Hiroki Kuroda,1 Luis Fuentealba, Atsushi Ikeda, (MAPK) known as extracellular signal-regulated protein 2 kinase (ERK) via the Ras pathway, and in this way causes Bruno Reversade, and E.M. De Robertis neural induction. Howard Hughes Medical Institute and Department Two disparate views dominate the neural induction of Biological Chemistry, University of California, field at present. Work in the chick embryo has stressed Los Angeles, California 90095-1662, USA the importance of FGF signaling, whereas work in Xeno- pus has tended to emphasize the requirement for anti- Xenopus embryonic ectodermal cells dissociated for BMPs in neural induction (Harland 2000; Stern 2004). three or more hours differentiate into neural tissue in- We have argued that these apparently conflicting obser- stead of adopting their normal epidermal fate. This de- vations can be reconciled through a molecular mecha- nism in which Ras/MAPK phosphorylation regulates the fault type of neural induction occurs in the absence of BMP transducers Smad1/5/8 (De Robertis and Kuroda Spemann’s organizer signals and is thought to be caused 2004).
    [Show full text]
  • Diapositive 1
    Apports des nouvelles technologies de la génomique dans les maladies rares Judith Melki Inserm UMR-1169 & University of Paris Sud CHSF, CHU Bicêtre [email protected] 7681 ccatcttctc tttgtgcatg ttggtctccg tgtcccaatt tcccctttct atagggactg cagtcctaat gaattagacc ccaacaaacg acctgatatt aacttgatta cctccataaa 7801 gatcctattt ctaaataagg ccacattttt ttgagatact aggaattagg acatcaatgt atcttttatg tgacagacat ttcaacccat tagagttacc taacctccct cctaacacca 7921 cttccccttt ataaaatgag gataaaagtg ctgacctcac agggctgtgg agaacctggg gctatgcatg tagaaggatt agcacagtgc ctggcacatg gctggaaggc atcaaatgtt 8041 agctagtatt attatgaaat ggggatatag agccttagag ctcaatttat tttgctttgc ttatacagaa gtccatatgg ataacatttt cctccaactc taaagggcat aatgattttt 8161 cataacagcg taagttgatt tttacatctt gtactttaca aaggaactat atatttgaat aaaatttact ttttatttga gtattgccat gtattcatac tatgatacaa ttgccttgaa 8281 taaatacctt actcccagta agtaaataaa ccctaaatgt taaaaatctg aacaatttaa acatggctag aaaatgcacc ttctatatta ttcctaaaat aaaagaaata aaggctctaa 8401 aatgcaatat tgaattcccc caaccatgct gatgtaggta aactgtattt cagatattgg gaaatagcct cataaactga gaagaacacg gcttttagat tcaagtacat atggattcaa 8521 cttccacctt tacccctaca gctctgtgac cagtgggaag ttatgtagct ttgttcagcc ttggtttctt catctgcgaa attaggaaaa taatactcct tcaaaagtga gagagcgtaa 8641 cctgcagtgg atgaatggat aaacaaaatg tgctatgtac atataatgga atattattca gccttaaaaa ggaaggaaat tctgacacac gctataacat ggattaacct tgagaacatt 8761 atgctaagtg aaataaacca gtcatcaata gacagatact gtattattcc acttatgtga ggtacctaaa gtcatcaaat tcatagaggt aaaaaacata aaggcttttg ccaaggtcca 8881 gggggagggt agaatgagga
    [Show full text]
  • R-Spondin Signalling Is Essential for the Maintenance And
    RESEARCH ARTICLE R-spondin signalling is essential for the maintenance and differentiation of mouse nephron progenitors Valerie PI Vidal1, Fariba Jian-Motamedi1, Samah Rekima1, Elodie P Gregoire1, Emmanuelle Szenker-Ravi2, Marc Leushacke2, Bruno Reversade2, Marie-Christine Chaboissier1, Andreas Schedl1* 1Universite´ Coˆte d’Azur, Inserm, CNRS, Institut de Biologie Valrose, Nice, France; 2Institute of Medical Biology, A*STAR, Singapore, Singapore Abstract During kidney development, WNT/b-catenin signalling has to be tightly controlled to ensure proliferation and differentiation of nephron progenitor cells. Here, we show in mice that the signalling molecules RSPO1 and RSPO3 act in a functionally redundant manner to permit WNT/b- catenin signalling and their genetic deletion leads to a rapid decline of nephron progenitors. By contrast, tissue specific deletion in cap mesenchymal cells abolishes mesenchyme to epithelial transition (MET) that is linked to a loss of Bmp7 expression, absence of SMAD1/5 phosphorylation and a concomitant failure to activate Lef1, Fgf8 and Wnt4, thus explaining the observed phenotype on a molecular level. Surprisingly, the full knockout of LGR4/5/6, the cognate receptors of R-spondins, only mildly affects progenitor numbers, but does not interfere with MET. Taken together our data demonstrate key roles for R-spondins in permitting stem cell maintenance and differentiation and reveal Lgr-dependent and independent functions for these ligands during kidney formation. *For correspondence: [email protected] Introduction Nephron endowment is a critical factor for renal health and low number of nephrons have been asso- Competing interests: The ciated with chronic kidney disease and hypertension (Bertram et al., 2011). In mammals, nephro- authors declare that no genesis is restricted to the developmental period and involves a dedicated nephrogenic niche at the competing interests exist.
    [Show full text]
  • Driven by Curiosity Under One Roof
    WINTER 2012|2013 ISSUE 23 encounters PAGE 13 Deciphering life PAGE 9 Under one roof PAGE 3 Driven by curiosity ANNIVERSARY EMBO to celebrate FEATURE How to help scientists FEATURE 120 past and present EMBO Fellows 50th anniversary in 2014. improve their management skills. attend meeting at Rockefeller University. PAGE 2 PAGE 7 PAGE 5 www.embo.org EMBO 50TH ANNIVERSARY EMBO to celebrate 50th anniversary in 2014 2014 is the 50th anniversary of EMBO and a full programme of events and activities are planned throughout the year. The 50th anniversary is an opportunity to look back on achievements and reflect on progress. It is also a time to celebrate and take a glimpse into the future. MBO, which was founded in 1964, will 2014 is also the 50th anniversary of FEBS, and of these projects is a collection of interviews with celebrate its 50th anniversary in 2014. its French member society, the Société française 10 scientists who have witnessed and influenced EDiverse activities and events are planned to de biochimie et de biologie moléculaire (SFBBM), the history of molecular biology and EMBO. highlight the contributions that EMBO has made will be 100 years old. Instead of holding separate Science writer Georgina Ferry will conduct and to the life sciences over its 50 years of existence – annual conferences, FEBS, EMBO and SFBBM write up the interviews. She is the author of such from talks and meetings to interviews and publi- will celebrate together in 2014 by holding a joint- books as Max Perutz and the Secret of Life and cations.
    [Show full text]
  • DPP9 Deficiency: an Inflammasomopathy ​ ​ Which Can Be Rescued by Lowering NLRP1/IL-1 Signaling
    medRxiv preprint doi: https://doi.org/10.1101/2021.01.31.21250067; this version posted February 3, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. DPP9 deficiency: an Inflammasomopathy ​ ​ which can be rescued by lowering NLRP1/IL-1 signaling 1,2,$ 3,$ 4,$ 4 Cassandra R. HARAPAS ,​ Kim S. ROBINSON ,​ Kenneth LAY ,​ Jasmine WONG ,​ ​ ​ ​ ​ 5 6,7,8 6 Annick RAAS-ROTHSCHILD ,​ Bertrand BOISSON ,​ Scott B. DRUTMAN ,​ Pawat ​ ​ ​ 1,2 9 10 1,2 LAOHAMONTHONKUL ,​ Devon BONNER ,​ Mark GORRELL ,​ Sophia DAVIDSON ,​ ​ ​ ​ ​ 1,2 11 12 Chien-Hsiung YU ,​ Hulya KAYSERILI ,​ Nevin HATIPOGLU ,​ Jean-Laurent ​ ​ ​ 6,7,8,13,14 15 3,* CASANOVA ,​ Jonathan A. BERNSTEIN ,​ Franklin L. ZHONG ,​ Seth L. ​ ​ ​ 1,2,* 4,10,16* MASTERS ,​ Bruno REVERSADE ​ ​ Affiliations: 1. Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia 2. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia 3. SRIS, A*STAR, Singapore 4. Genome Institute of Singapore (GIS), A*STAR, Singapore 5. The Institute for Rare Diseases, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel 6. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The ​ Rockefeller University, New York, USA 7. Paris​ University, Imagine Institute, Paris, France ​ 8. Laboratory of Human Genetics of Infectious Disease, Necker Branch, INSERM U1163, Paris, France 9. Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, ​ USA.
    [Show full text]
  • Early ACCESS Diagnosed Conditions List
    Iowa Early ACCESS Diagnosed Conditions Eligibility List List adapted with permission from Early Intervention Colorado To search for a specific word type "Ctrl F" to use the "Find" function. Is this diagnosis automatically eligible for Early Medical Diagnosis Name Other Names for the Diagnosis and Additional Diagnosis Information ACCESS? 6q terminal deletion syndrome Yes Achondrogenesis I Parenti-Fraccaro Yes Achondrogenesis II Langer-Saldino Yes Schinzel Acrocallosal syndrome; ACLS; ACS; Hallux duplication, postaxial polydactyly, and absence of the corpus Acrocallosal syndrome, Schinzel Type callosum Yes Acrodysplasia; Arkless-Graham syndrome; Maroteaux-Malamut syndrome; Nasal hypoplasia-peripheral dysostosis-intellectual disability syndrome; Peripheral dysostosis-nasal hypoplasia-intellectual disability (PNM) Acrodysostosis syndrome Yes ALD; AMN; X-ALD; Addison disease and cerebral sclerosis; Adrenomyeloneuropathy; Siemerling-creutzfeldt disease; Bronze schilder disease; Schilder disease; Melanodermic Leukodystrophy; sudanophilic leukodystrophy; Adrenoleukodystrophy Pelizaeus-Merzbacher disease Yes Agenesis of Corpus Callosum Absence of the corpus callosum; Hypogenesis of the corpus callosum; Dysplastic corpus callosum Yes Agenesis of Corpus Callosum and Chorioretinal Abnormality; Agenesis of Corpus Callosum With Chorioretinitis Abnormality; Agenesis of Corpus Callosum With Infantile Spasms And Ocular Anomalies; Chorioretinal Anomalies Aicardi syndrome with Agenesis Yes Alexander Disease Yes Allan Herndon syndrome Allan-Herndon-Dudley
    [Show full text]
  • Mitochondrial Peptide BRAWNIN Is Essential for Vertebrate Respiratory Complex III Assembly
    ARTICLE https://doi.org/10.1038/s41467-020-14999-2 OPEN Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly Shan Zhang1, Boris Reljić 2,12, Chao Liang 1,12, Baptiste Kerouanton1,12, Joel Celio Francisco 3, Jih Hou Peh1, Camille Mary 4, Narendra Suhas Jagannathan 5, Volodimir Olexiouk 6, Claire Tang1, Gio Fidelito 1, Srikanth Nama7, Ruey-Kuang Cheng8, Caroline Lei Wee 9, Loo Chien Wang9, Paula Duek Roggli 10, Prabha Sampath 11, Lydie Lane 4, Enrico Petretto 5, Radoslaw M. Sobota 9, Suresh Jesuthasan 8,9, Lisa Tucker-Kellogg 3,5, Bruno Reversade 7,9, Gerben Menschaert6, Lei Sun 1, David A. Stroud 2 & ✉ Lena Ho 1,7 1234567890():,; The emergence of small open reading frame (sORF)-encoded peptides (SEPs) is rapidly expanding the known proteome at the lower end of the size distribution. Here, we show that the mitochondrial proteome, particularly the respiratory chain, is enriched for small proteins. Using a prediction and validation pipeline for SEPs, we report the discovery of 16 endogenous nuclear encoded, mitochondrial-localized SEPs (mito-SEPs). Through functional prediction, proteomics, metabolomics and metabolic flux modeling, we demonstrate that BRAWNIN, a 71 a.a. peptide encoded by C12orf73, is essential for respiratory chain complex III (CIII) assembly. In human cells, BRAWNIN is induced by the energy-sensing AMPK pathway, and its depletion impairs mitochondrial ATP production. In zebrafish, Brawnin deletion causes complete CIII loss, resulting in severe growth retardation, lactic acidosis and early death. Our findings demonstrate that BRAWNIN is essential for vertebrate oxidative phosphorylation. We propose that mito-SEPs are an untapped resource for essential regulators of oxidative metabolism.
    [Show full text]