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

Jil D. Stegmann; Jeshurun C. Kalanithy; Gabriel C. Dworschak; Nina Ishorst; Enrico Mingardo; Filipa M. Lopes; Yee Mang Ho; Phillip Grote; Tobias T. Lindenberg; Öznur Yilmaz; Khadija Channab; Steve Seltzsam; Shirlee Shril; Friedhelm Hildebrandt; Felix Boschann; André Heinen; Angad Jolly; Katherine Myers; Kim McBride; Mir Reza Bekheirnia; Nasim Bekheirnia; Marcello Scala; Manuela Morleo; Vincenzo Nigro; Annalaura Torella; Michele Pinelli; Valeria Capra; Andrea Accogli; Silvia Maitz; Alice Spano; Rory J. Olson; Eric W. Klee; Brendan C. Lanpher; Se Song Jang; Jong Hee Chae; Philipp Steinbauer; Dietmar Rieder; Andreas R. Janecke; Julia Vodopiutz; Ida Vogel; Jenny Blechingberg; Jennifer L. Cohen; Kacie Riley; Victoria Klee; Laurence E. Walsh; Matthias Begemann; Miriam Elbracht; Thomas Eggermann; Arzu Stoppe; Kyra Stuurman; Marjon van Slegtenhorst; Tahsin Stefan Barakat; Maureen S. Mulhern; Tristan T. Sands; Cheryl Cytrynbaum; Rosanna Weksberg; Federica Isidori; Tommaso Pippucci; Giulia Severi; Francesca Montanari; Michael C. Kruer; Somayeh Bakhtiari; Hossein Darvish; Heiko Reutter; Gregor Hagelueken; Matthias Geyer; Adrian S. Woolf; Jennifer E. Posey; James R. Lupski; Benjamin Odermatt; Alina C. Hilger

doi:10.1038/s41525-024-00398-9

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

Jil D. Stegmann, Jeshurun C. Kalanithy, Gabriel C. Dworschak, Nina Ishorst, Enrico Mingardo, Filipa M. Lopes, Yee Mang Ho, Phillip Grote, Tobias T. Lindenberg, Öznur Yilmaz, Khadija Channab, Steve Seltzsam, Shirlee Shril, Friedhelm Hildebrandt, Felix Boschann, André Heinen, Angad Jolly, Katherine Myers, Kim McBride, Mir Reza BekheirniaNasim Bekheirnia, Marcello Scala, Manuela Morleo, Vincenzo Nigro, Annalaura Torella, Michele Pinelli, Valeria Capra, Andrea Accogli, Silvia Maitz, Alice Spano, Rory J. Olson, Eric W. Klee, Brendan C. Lanpher, Se Song Jang, Jong Hee Chae, Philipp Steinbauer, Dietmar Rieder, Andreas R. Janecke, Julia Vodopiutz, Ida Vogel, Jenny Blechingberg, Jennifer L. Cohen, Kacie Riley, Victoria Klee, Laurence E. Walsh, Matthias Begemann, Miriam Elbracht, Thomas Eggermann, Arzu Stoppe, Kyra Stuurman, Marjon van Slegtenhorst, Tahsin Stefan Barakat, Maureen S. Mulhern, Tristan T. Sands, Cheryl Cytrynbaum, Rosanna Weksberg, Federica Isidori, Tommaso Pippucci, Giulia Severi, Francesca Montanari, Michael C. Kruer, Somayeh Bakhtiari, Hossein Darvish, Heiko Reutter, Gregor Hagelueken, Matthias Geyer, Adrian S. Woolf, Jennifer E. Posey, James R. Lupski, Benjamin Odermatt, Alina C. Hilger

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	18
Journal	npj Genomic Medicine
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41525-024-00398-9
State	Published - Dec 2024

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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10.1038/s41525-024-00398-9

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Stegmann, J. D., Kalanithy, J. C., Dworschak, G. C., Ishorst, N., Mingardo, E., Lopes, F. M., Ho, Y. M., Grote, P., Lindenberg, T. T., Yilmaz, Ö., Channab, K., Seltzsam, S., Shril, S., Hildebrandt, F., Boschann, F., Heinen, A., Jolly, A., Myers, K., McBride, K., ... Hilger, A. C. (2024). Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies. npj Genomic Medicine, 9(1), Article 18. https://doi.org/10.1038/s41525-024-00398-9

Stegmann, JD, Kalanithy, JC, Dworschak, GC, Ishorst, N, Mingardo, E, Lopes, FM, Ho, YM, Grote, P, Lindenberg, TT, Yilmaz, Ö, Channab, K, Seltzsam, S, Shril, S, Hildebrandt, F, Boschann, F, Heinen, A, Jolly, A, Myers, K, McBride, K, Bekheirnia, MR, Bekheirnia, N, Scala, M, Morleo, M, Nigro, V, Torella, A, Pinelli, M, Capra, V, Accogli, A, Maitz, S, Spano, A, Olson, RJ, Klee, EW , Lanpher, BC, Jang, SS, Chae, JH, Steinbauer, P, Rieder, D, Janecke, AR, Vodopiutz, J, Vogel, I, Blechingberg, J, Cohen, JL, Riley, K, Klee, V, Walsh, LE, Begemann, M, Elbracht, M, Eggermann, T, Stoppe, A, Stuurman, K, van Slegtenhorst, M, Barakat, TS, Mulhern, MS, Sands, TT, Cytrynbaum, C, Weksberg, R, Isidori, F, Pippucci, T, Severi, G, Montanari, F, Kruer, MC, Bakhtiari, S, Darvish, H, Reutter, H, Hagelueken, G, Geyer, M, Woolf, AS, Posey, JE, Lupski, JR, Odermatt, B & Hilger, AC 2024, 'Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies', npj Genomic Medicine, vol. 9, no. 1, 18. https://doi.org/10.1038/s41525-024-00398-9

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title = "Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies",

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.",

author = "Stegmann, {Jil D.} and Kalanithy, {Jeshurun C.} and Dworschak, {Gabriel C.} and Nina Ishorst and Enrico Mingardo and Lopes, {Filipa M.} and Ho, {Yee Mang} and Phillip Grote and Lindenberg, {Tobias T.} and {\"O}znur Yilmaz and Khadija Channab and Steve Seltzsam and Shirlee Shril and Friedhelm Hildebrandt and Felix Boschann and Andr{\'e} Heinen and Angad Jolly and Katherine Myers and Kim McBride and Bekheirnia, {Mir Reza} and Nasim Bekheirnia and Marcello Scala and Manuela Morleo and Vincenzo Nigro and Annalaura Torella and Michele Pinelli and Valeria Capra and Andrea Accogli and Silvia Maitz and Alice Spano and Olson, {Rory J.} and Klee, {Eric W.} and Lanpher, {Brendan C.} and Jang, {Se Song} and Chae, {Jong Hee} and Philipp Steinbauer and Dietmar Rieder and Janecke, {Andreas R.} and Julia Vodopiutz and Ida Vogel and Jenny Blechingberg and Cohen, {Jennifer L.} and Kacie Riley and Victoria Klee and Walsh, {Laurence E.} and Matthias Begemann and Miriam Elbracht and Thomas Eggermann and Arzu Stoppe and Kyra Stuurman and {van Slegtenhorst}, Marjon and Barakat, {Tahsin Stefan} and Mulhern, {Maureen S.} and Sands, {Tristan T.} and Cheryl Cytrynbaum and Rosanna Weksberg and Federica Isidori and Tommaso Pippucci and Giulia Severi and Francesca Montanari and Kruer, {Michael C.} and Somayeh Bakhtiari and Hossein Darvish and Heiko Reutter and Gregor Hagelueken and Matthias Geyer and Woolf, {Adrian S.} and Posey, {Jennifer E.} and Lupski, {James R.} and Benjamin Odermatt and Hilger, {Alina C.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41525-024-00398-9",

language = "English (US)",

volume = "9",

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T1 - Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies

AU - Stegmann, Jil D.

AU - Kalanithy, Jeshurun C.

AU - Dworschak, Gabriel C.

AU - Ishorst, Nina

AU - Mingardo, Enrico

AU - Lopes, Filipa M.

AU - Ho, Yee Mang

AU - Grote, Phillip

AU - Lindenberg, Tobias T.

AU - Yilmaz, Öznur

AU - Channab, Khadija

AU - Seltzsam, Steve

AU - Shril, Shirlee

AU - Hildebrandt, Friedhelm

AU - Boschann, Felix

AU - Heinen, André

AU - Jolly, Angad

AU - Myers, Katherine

AU - McBride, Kim

AU - Bekheirnia, Mir Reza

AU - Bekheirnia, Nasim

AU - Scala, Marcello

AU - Morleo, Manuela

AU - Nigro, Vincenzo

AU - Torella, Annalaura

AU - Pinelli, Michele

AU - Capra, Valeria

AU - Accogli, Andrea

AU - Maitz, Silvia

AU - Spano, Alice

AU - Olson, Rory J.

AU - Klee, Eric W.

AU - Lanpher, Brendan C.

AU - Jang, Se Song

AU - Chae, Jong Hee

AU - Steinbauer, Philipp

AU - Rieder, Dietmar

AU - Janecke, Andreas R.

AU - Vodopiutz, Julia

AU - Vogel, Ida

AU - Blechingberg, Jenny

AU - Cohen, Jennifer L.

AU - Riley, Kacie

AU - Klee, Victoria

AU - Walsh, Laurence E.

AU - Begemann, Matthias

AU - Elbracht, Miriam

AU - Eggermann, Thomas

AU - Stoppe, Arzu

AU - Stuurman, Kyra

AU - van Slegtenhorst, Marjon

AU - Barakat, Tahsin Stefan

AU - Mulhern, Maureen S.

AU - Sands, Tristan T.

AU - Cytrynbaum, Cheryl

AU - Weksberg, Rosanna

AU - Isidori, Federica

AU - Pippucci, Tommaso

AU - Severi, Giulia

AU - Montanari, Francesca

AU - Kruer, Michael C.

AU - Bakhtiari, Somayeh

AU - Darvish, Hossein

AU - Reutter, Heiko

AU - Hagelueken, Gregor

AU - Geyer, Matthias

AU - Woolf, Adrian S.

AU - Posey, Jennifer E.

AU - Lupski, James R.

AU - Odermatt, Benjamin

AU - Hilger, Alina C.

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41525-024-00398-9

DO - 10.1038/s41525-024-00398-9

M3 - Article

AN - SCOPUS:85186632646

SN - 2056-7944

VL - 9

JO - npj Genomic Medicine

JF - npj Genomic Medicine

IS - 1

M1 - 18

ER -

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

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