open access publication

Article, 2024

Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies

Npj Genomic Medicine, ISSN 2056-7944, Volume 9, 1, 10.1038/s41525-024-00398-9

Contributors

Stegmann J.D. 0000-0002-1287-0308 (Corresponding author) [1] Kalanithy J.C. [1] Dworschak G.C. 0000-0003-0015-6964 [1] [2] Ishorst N. 0000-0001-9836-554X [1] Mingardo E. [1] Lopes F.M. [3] Ho Y.M. [3] Grote P. 0000-0002-9254-1458 [4] Lindenberg T.T. [1] Yilmaz O. [1] Channab K. [1] Seltzsam S. [5] Shril S. [5] Hildebrandt F. 0000-0003-3845-3489 [5] Boschann F. 0000-0001-9410-9290 [6] Heinen A. [7] Jolly A. [8] Myers K. [9] McBride K.L. [9] Bekheirnia M.R. [8] [10] Bekheirnia N. [8] [10] Scala M. 0000-0003-2194-7239 [11] [12] Morleo M. [13] [14] Nigro V. 0000-0002-3378-5006 [13] [14] Torella A. 0000-0003-2479-6018 [13] [14] Pinelli M. 0000-0002-5927-1185 [14] [15] Capra V. 0000-0002-3097-0388 [12] Accogli A. 0000-0001-8724-6721 [16] [17] Maitz S. [18] Spano A. Olson R.J. [19] Klee E.W. 0000-0003-2946-5795 [19] Lanpher B.C. [19] Jang S.S. [20] Chae J.-H. [20] [21] Steinbauer P. [22] Rieder D. [23] Janecke A.R. 0000-0001-7155-0315 [23] Vodopiutz J. 0000-0002-8087-7026 [22] Vogel I. 0000-0002-1125-0393 [24] [25] Blechingberg J. 0000-0002-4110-7459 [25] Cohen J.L. [26] Riley K. [27] Klee V. [28] Walsh L.E. [28] Begemann M. 0000-0002-4659-8437 [29] Elbracht M. [29] Eggermann T. 0000-0002-8419-0264 [29] Stoppe A. [29] Stuurman K.E. [30] van Slegtenhorst M. [30] Barakat T.S. 0000-0003-1231-1562 [30] Mulhern M.S. [31] Sands T. 0000-0001-7285-1195 [31] Cytrynbaum C. 0000-0002-3742-1250 [32] [33] Weksberg R. 0000-0002-6501-4150 [32] [33] Isidori F. [34] Pippucci T. [34] Severi G. 0000-0001-8184-865X [34] Montanari F. [34] Kruer M.C. 0000-0002-1373-7891 [35] [36] Bakhtiari S. [35] [36] Darvish H. [37] Reutter H. 0000-0002-3591-5265 [1] [38] Hagelueken G. [2] Geyer M. [2] Woolf A.S. 0000-0001-5541-1358 [3] [39] Posey J.E. 0000-0003-4814-6765 [8] Lupski J.R. 0000-0001-9907-9246 [8] [10] Odermatt B. 0000-0002-9361-2772 [1] Hilger A.C. 0000-0002-0354-7584 (Corresponding author) [38] [40]

Affiliations

  1. [1] Medical Faculty
    2. [NORA names: Germany; Europe, EU; OECD];
  2. [2] University Hospital Bonn
    3. [NORA names: Germany; Europe, EU; OECD];
  3. [3] University of Manchester
    4. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  4. [4] Georg-Speyer-Haus
    5. [NORA names: Germany; Europe, EU; OECD];
  5. [5] Harvard Medical School
    6. [NORA names: United States; America, North; OECD];

Abstract

CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation.

Funders

  • Muscular Dystrophy Association
  • Baylor College of Medicine and Baylor Genetics Laboratories
  • Deutsche Forschungsgemeinschaft
  • Eva Luise und Horst Köhler Stiftung
  • National Institute of Neurological Disorders and Stroke
  • Novo Nordisk Fonden
  • Rheinische Friedrich-Wilhelms-Universität Bonn
  • Telethon Undiagnosed Diseases Program
  • BONFOR
  • MCR-NIHR
  • National Institutes of Health
  • Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg
  • Medical Research Council
  • ZonMW Veni
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
  • National Human Genome Research Institute
  • European Zebrafish Resource Centre
  • Begg Family Foundation
  • BonnNI
  • Else Kröner-Fresenius-Stiftung
  • Friedrich-Alexander-Universität Erlangen-Nürnberg
  • Herbert-Reeck foundation
  • Erasmus Medisch Centrum

Data Provider: Elsevier

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