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

Jil D Stegmann; Jeshurun C Kalanithy; Gabriel C Dworschak; TUDP consortium; 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; Kyra Stuurman; Marjon van Slegtenhorst

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, TUDP consortium, 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 McBrideMir 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, Kyra Stuurman, Marjon van Slegtenhorst

^*Corresponding author for this work

Clinical Genetics

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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
Article number	18
Journal	npj Genomic Medicine
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41525-024-00398-9
Publication status	Published - Dec 2024

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Publisher Copyright:
© The Author(s) 2024.

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Stegmann, J. D., Kalanithy, J. C., Dworschak, G. C., TUDP consortium, 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., ... van Slegtenhorst, M. (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

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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 {TUDP consortium} 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 Jong-Hee Chae 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 Kyra Stuurman and {van Slegtenhorst}, Marjon",

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

year = "2024",

month = dec,

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

language = "English",

volume = "9",

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Stegmann, JD, Kalanithy, JC, Dworschak, GC, TUDP consortium, 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, J-H, 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, Stuurman, K & van Slegtenhorst, M 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

TY - JOUR

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 - TUDP consortium

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 - Stuurman, Kyra

AU - van Slegtenhorst, Marjon

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

C2 - 38429302

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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