Research ExplorerPublicationsAXIN1 bi-allelic variants disrupting the C-terminal DIX doma...

AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia

Standard

AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia. / Terhal, Paulien; Venhuizen, Anton J; Lessel, Davor; Tan, Wen-Hann; Alswaid, Abdulrahman; Grün, Regina; Alzaidan, Hamad I; von Kroge, Simon; Ragab, Nada; Hempel, Maja; Kubisch, Christian; Novais, Eduardo; Cristobal, Alba; Tripolszki, Kornelia; Bauer, Peter; Fischer-Zirnsak, Björn; Nievelstein, Rutger A J; van Dijk, Atty; Nikkels, Peter; Oheim, Ralf; Hahn, Heidi; Bertoli-Avella, Aida; Maurice, Madelon M; Kornak, Uwe.

In: AM J HUM GENET, Vol. 110, No. 9, 07.09.2023, p. 1470-1481.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Terhal, P, Venhuizen, AJ, Lessel, D, Tan, W-H, Alswaid, A, Grün, R, Alzaidan, HI, von Kroge, S, Ragab, N, Hempel, M, Kubisch, C, Novais, E, Cristobal, A, Tripolszki, K, Bauer, P, Fischer-Zirnsak, B, Nievelstein, RAJ, van Dijk, A, Nikkels, P, Oheim, R, Hahn, H, Bertoli-Avella, A, Maurice, MM & Kornak, U 2023, 'AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia', AM J HUM GENET, vol. 110, no. 9, pp. 1470-1481. https://doi.org/10.1016/j.ajhg.2023.07.011

APA

Terhal, P., Venhuizen, A. J., Lessel, D., Tan, W-H., Alswaid, A., Grün, R., Alzaidan, H. I., von Kroge, S., Ragab, N., Hempel, M., Kubisch, C., Novais, E., Cristobal, A., Tripolszki, K., Bauer, P., Fischer-Zirnsak, B., Nievelstein, R. A. J., van Dijk, A., Nikkels, P., ... Kornak, U. (2023). AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia. AM J HUM GENET, 110(9), 1470-1481. https://doi.org/10.1016/j.ajhg.2023.07.011

Vancouver

Terhal P, Venhuizen AJ, Lessel D, Tan W-H, Alswaid A, Grün R et al. AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia. AM J HUM GENET. 2023 Sep 7;110(9):1470-1481. https://doi.org/10.1016/j.ajhg.2023.07.011

Bibtex

@article{bd9479705dc6439a9cecfac5e9324183,
title = "AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia",
abstract = "Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies. In line with AXIN1 being a central component of the β-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity. All three AXIN1-truncating variants resulted in reduced protein levels and impaired AXIN1 polymerization mediated by its C-terminal DIX domain but partially retained Wnt-inhibitory function upon overexpression. Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems. Our data suggest that AXIN1 coordinates the action of osteoblasts and osteoclasts and that tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic variants.",
keywords = "Humans, Tankyrases/genetics, Hip Dislocation, Axin Protein/genetics, Wnt Signaling Pathway/genetics, Osteosclerosis/genetics, beta Catenin/metabolism",
author = "Paulien Terhal and Venhuizen, {Anton J} and Davor Lessel and Wen-Hann Tan and Abdulrahman Alswaid and Regina Gr{\"u}n and Alzaidan, {Hamad I} and {von Kroge}, Simon and Nada Ragab and Maja Hempel and Christian Kubisch and Eduardo Novais and Alba Cristobal and Kornelia Tripolszki and Peter Bauer and Bj{\"o}rn Fischer-Zirnsak and Nievelstein, {Rutger A J} and {van Dijk}, Atty and Peter Nikkels and Ralf Oheim and Heidi Hahn and Aida Bertoli-Avella and Maurice, {Madelon M} and Uwe Kornak",
note = "Copyright {\textcopyright} 2023 American Society of Human Genetics. All rights reserved.",
year = "2023",
month = sep,
day = "7",
doi = "10.1016/j.ajhg.2023.07.011",
language = "English",
volume = "110",
pages = "1470--1481",
journal = "AM J HUM GENET",
issn = "0002-9297",
publisher = "Cell Press",
number = "9",

}

RIS

TY - JOUR

T1 - AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia

AU - Terhal, Paulien

AU - Venhuizen, Anton J

AU - Lessel, Davor

AU - Tan, Wen-Hann

AU - Alswaid, Abdulrahman

AU - Grün, Regina

AU - Alzaidan, Hamad I

AU - von Kroge, Simon

AU - Ragab, Nada

AU - Hempel, Maja

AU - Kubisch, Christian

AU - Novais, Eduardo

AU - Cristobal, Alba

AU - Tripolszki, Kornelia

AU - Bauer, Peter

AU - Fischer-Zirnsak, Björn

AU - Nievelstein, Rutger A J

AU - van Dijk, Atty

AU - Nikkels, Peter

AU - Oheim, Ralf

AU - Hahn, Heidi

AU - Bertoli-Avella, Aida

AU - Maurice, Madelon M

AU - Kornak, Uwe

N1 - Copyright © 2023 American Society of Human Genetics. All rights reserved.

PY - 2023/9/7

Y1 - 2023/9/7

N2 - Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies. In line with AXIN1 being a central component of the β-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity. All three AXIN1-truncating variants resulted in reduced protein levels and impaired AXIN1 polymerization mediated by its C-terminal DIX domain but partially retained Wnt-inhibitory function upon overexpression. Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems. Our data suggest that AXIN1 coordinates the action of osteoblasts and osteoclasts and that tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic variants.

AB - Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies. In line with AXIN1 being a central component of the β-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity. All three AXIN1-truncating variants resulted in reduced protein levels and impaired AXIN1 polymerization mediated by its C-terminal DIX domain but partially retained Wnt-inhibitory function upon overexpression. Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems. Our data suggest that AXIN1 coordinates the action of osteoblasts and osteoclasts and that tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic variants.

KW - Humans

KW - Tankyrases/genetics

KW - Hip Dislocation

KW - Axin Protein/genetics

KW - Wnt Signaling Pathway/genetics

KW - Osteosclerosis/genetics

KW - beta Catenin/metabolism

U2 - 10.1016/j.ajhg.2023.07.011

DO - 10.1016/j.ajhg.2023.07.011

M3 - SCORING: Journal article

C2 - 37582359

VL - 110

SP - 1470

EP - 1481

JO - AM J HUM GENET

JF - AM J HUM GENET

SN - 0002-9297

IS - 9

ER -