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, Page 18, 10.1038/s41525-024-00398-9

Contributors

Stegmann, Jil D (Corresponding author) [1] Kalanithy, Jeshurun C [1] Dworschak, Gabriel Clemens 0000-0003-0015-6964 [1] [2] Ishorst, Nina [1] Mingardo, Enrico 0000-0002-2562-0615 [1] Lopes, Filipa M [3] Ho, Yee Mang [3] Grote, Phillip 0000-0002-9254-1458 [4] Lindenberg, Tobias T [1] Yilmaz, Öznur [1] Channab, Khadija [1] Seltzsam, Steve 0000-0002-1269-6899 [5] [6] Shril, Shirlee [5] [6] Hildebrandt, Friedhelm [5] [6] Boschann, Felix 0000-0001-9410-9290 [7] Heinen, André [8] Jolly, Angad 0000-0002-5663-1157 [9] Myers, Katherine [10] [11] Mcbride, Kim Lewis 0000-0002-8407-8942 [10] [11] Bekheirnia, Mir Reza [9] [12] Bekheirnia, Nasim [9] [12] Scala, Marcello 0000-0003-2194-7239 [13] [14] Morleo, Manuela 0000-0002-7553-3245 [15] [16] Nigro, Vincenzo 0000-0002-3378-5006 [15] [16] Torella, Anna Laura 0000-0003-2479-6018 [15] [16] Pinelli, Michele 0000-0002-5927-1185 [16] [17] Capra, Valeria [18] Accogli, Andrea [19] Maitz, Silvia [20] Spano, Alice [21] Olson, Rory J. [22] Klee, Eric W 0000-0003-2946-5795 [22] Lanpher, Brendan C. [22] Jang, Se Song 0000-0002-6299-0228 [23] Chae, Jong-Hee [23] [24] Steinbauer, Philipp 0000-0001-7961-327X [25] Rieder, Dietmar 0000-0003-1754-690X [26] Janecke, Andreas Robert 0000-0001-7155-0315 [26] Vodopiutz, Julia 0000-0002-8087-7026 [25] Vogel, Ida 0000-0002-1125-0393 [27] [28] Blechingberg, Jenny 0000-0002-4110-7459 [28] Cohen, Jennifer L. [29] Riley, Kacie [30] Klee, Victoria [31] Walsh, Laurence E 0000-0003-4623-1317 [31] Begemann, Matthias 0000-0002-4659-8437 [32] Elbracht, Miriam 0000-0001-5088-1369 [32] Eggermann, Thomas [32] Stoppe, Arzu [32] Stuurman, Kyra Eva [33] Van Slegtenhorst, Marjon A [33] Barakat, Tahsin Stefan 0000-0003-1231-1562 [33] Mulhern, Maureen S [34] Sands, Tristan T [34] [35] Cytrynbaum, Cheryl S [36] [37] Weksberg, Rosanna A 0000-0002-6501-4150 [36] [37] Isidori, Federica 0000-0001-5934-3030 [38] Pippucci, Tommaso 0000-0001-7737-7963 [38] Severi, Giulia [38] Montanari, Francesca [38] Kruer, Michael C 0000-0002-1373-7891 [39] [40] Bakhtiari, Somayeh [39] [40] Darvish, Hossein 0000-0001-7515-9225 [41] Reutter, Heiko Martin 0000-0002-3591-5265 [1] [42] Hagelueken, Gregor 0000-0001-8781-5664 [1] [2] Geyer, Matthias 0000-0002-7718-5002 [1] [2] Woolf, Adrian Spencer 0000-0001-5541-1358 [3] [43] Posey, Jennifer Ellen 0000-0003-4814-6765 [9] Lupski, James R 0000-0001-9907-9246 [9] [12] Odermatt, Benjamin [1] Hilger, Alina Christine 0000-0002-0354-7584 (Corresponding author) [42] [44]

Affiliations

  1. [1] University of Bonn
    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] Boston Children's Hospital
    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.

Keywords

CAKUT, Celsr3, affected individuals, anomalies, bi-allelic variants, cell polarity proteins, central nervous system, central nervous system anomalies, computer simulations, congenital anomalies, embryonic role, experiments, expression, family, formation, identified variants, immunolocalization, individuals, kidney, lines, nervous system, penetration, phenotype, phenotypic expression, phenotypic spectrum, planar cell polarity proteins, polarity proteins, position, protein, protein structure, reporter lines, role, simulation, spectra, structure, suppression, system, tract, tract formation, transient suppression, urinary tract, urinary tract anomalies, variants, zebrafish reporter lines

Funders

  • Muscular Dystrophy Association
  • Dutch Research Council
  • Medical Research Council
  • National Institute of Neurological Disorders and Stroke
  • Stifterverband
  • National Human Genome Research Institute
  • Fresenius (Germany)
  • Telethon Foundation
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • Deutsche Forschungsgemeinschaft
  • National Institute for Health and Care Research
  • Netherlands Organisation for Health Research and Development
  • Novo Nordisk Foundation
  • European Commission

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