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

P Terhal, AJ Venhuizen, D Lessel (Co-author), WH Tan, A Alswaid, R Gruen, HI Alzaidan, S von Kroge, N Ragab, M Hempel, C Kubisch, E Novais, A Cristobal, K Tripolszki, P Bauer, B Fischer-Zirnsak, RAJ Nievelstein, A van Dijk, P Nikkels, R OheimH Hahn, A Bertoli-Avella, MM Maurice, U Kornak

Research output: Contribution to journalOriginal Article (Journal)peer-review

2 Citations (Web of Science)

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 he-matological anomalies. In line with AXIN1 being a central component of the j3-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity. All three AXIN1-trun-cating 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 in-hibitors can attenuate the effects of AXIN1 hypomorphic variants.
Original languageEnglish
Pages (from-to)1470-1481
Number of pages13
JournalAMERICAN JOURNAL OF HUMAN GENETICS
Volume110
Issue number9
DOIs
Publication statusPublished - 7 Sept 2023

Keywords

  • OSTEOPATHIA STRIATA
  • CRANIAL SCLEROSIS
  • MUTATIONS
  • BETA
  • DISEASE
  • FORM
  • Humans
  • Tankyrases/genetics
  • Osteosclerosis/genetics
  • Wnt Signaling Pathway/genetics
  • Hip Dislocation
  • Axin Protein/genetics
  • beta Catenin/metabolism
  • Mutations
  • Disease
  • Form
  • Osteopathia striata
  • Beta
  • Cranial sclerosis

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