AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia
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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, Jahrgang 110, Nr. 9, 07.09.2023, S. 1470-1481.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -