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

Terhal, Paulien A; Venhuizen, Anton J.; Lessel, Davor; Tan, Wen‐Hann; Alswaid, Abdulrahman; Grün, Regina; Alzaidan, Hamad; Kroge, Simon von; Ragab, Nada; Hempel, Maja; Kubisch, Christian; Novais, E.; Cristobal, Alba; Tripolszki, Kornélia; Bauer, Péter; Fischer-Zirnsak, Björn; Nievelstein, Rutger A.J.; Dijk, Anouk van; Nikkels, Peter G. J.; Oheim, Ralf; Hahn, Heidi; Bertoli‐Avella, Aida M.; Maurice, Madelon M.; Kornak, Uwe

doi:10.1016/j.ajhg.2023.07.011

Cited by 3 publications

(1 citation statement)

References 48 publications

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“…In a recent breakthrough, researchers have unveiled the manifestation of a human genetic disorder caused by AXIN1 mutations. In particular, bi-allelic variants disrupting the C-terminal DIX domain of AXIN1 were identified as causative factors for craniometadiaphyseal osteosclerosis with hip dysplasia [ 145 ]. Simultaneously, investigations in murine models have brought to the fore the pivotal role of AXIN1 in lower limb development.…”

Section: Introductionmentioning

confidence: 99%

The scaffold protein AXIN1: gene ontology, signal network, and physiological function

Qiu,

Sun,

Ning

et al. 2024

Cell Commun Signal

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AXIN1, has been initially identified as a prominent antagonist within the WNT/β-catenin signaling pathway, and subsequently unveiled its integral involvement across a diverse spectrum of signaling cascades. These encompass the WNT/β-catenin, Hippo, TGFβ, AMPK, mTOR, MAPK, and antioxidant signaling pathways. The versatile engagement of AXIN1 underscores its pivotal role in the modulation of developmental biological signaling, maintenance of metabolic homeostasis, and coordination of cellular stress responses. The multifaceted functionalities of AXIN1 render it as a compelling candidate for targeted intervention in the realms of degenerative pathologies, systemic metabolic disorders, cancer therapeutics, and anti-aging strategies. This review provides an intricate exploration of the mechanisms governing mammalian AXIN1 gene expression and protein turnover since its initial discovery, while also elucidating its significance in the regulation of signaling pathways, tissue development, and carcinogenesis. Furthermore, we have introduced the innovative concept of the AXIN1-Associated Phosphokinase Complex (AAPC), where the scaffold protein AXIN1 assumes a pivotal role in orchestrating site-specific phosphorylation modifications through interactions with various phosphokinases and their respective substrates.

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Section: Introductionmentioning

confidence: 99%

The scaffold protein AXIN1: gene ontology, signal network, and physiological function

Qiu,

Sun,

Ning

et al. 2024

Cell Commun Signal

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Craniotubular Dysplasia Ikegawa Type: Further Delineation of the Phenotype

van Ommeren,

Hoekstra,

van Gassen

et al. 2024

American J of Med Genetics Pt A

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Craniotubular Dysplasia Ikegawa type is a sclerosing bone disorder recently identified in five patients from four independent Indian families. It is caused by homozygous or compound heterozygous mutations in TMEM53. Deficient TMEM53 leads to overactive BMP signaling which promotes bone formation. Here, we present another three siblings with intronic mutations in TMEM53, identified by exome sequencing, from a Caucasian family. All three siblings displayed skeletal and radiographic features, similar to the earlier described individuals. All our patients had additional features such as cardiac and urogenital anomalies. Our results confirm the phenotype of CTDI. We discuss whether the additional features in our patients are separate from CTDI or reflect a broader spectrum of the syndrome.

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Levels of 91 circulating inflammatory proteins and risk of lumbar spine and pelvic fractures and peripheral ligament injuries: a two-sample mendelian randomization study

Huang,

Fu,

Yang

et al. 2024

J Orthop Surg Res

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Objective Lumbar spine and pelvic fractures(LPF) are combined with peripheral ligament injuries(PLI), frequently. It has been reported that the site of fracture injury is usually paralleled by the secretion of inflammatory proteins. This study aimed to investigate the causal relationship between 91 circulating inflammatory proteins and LPF and PLI by using a Two-sample Mendelian randomization (MR) analysis. Methods Single nucleotide polymorphisms (SNPs) associated with 91 circulating inflammatory proteins, as exposures were selected from a large genome-wide association study (GWAS). The genetic variant data for LPF and PLI as outcomes from the FinnGen consortium. The inverse-variance-weighted (IVW) method was utilized as the main analysis for exposures and outcomes. In addition, the final results were reinforced by the methods of MR Egger, weighted median, simple mode, and weighted mode. The sensitivity analyses were used to validate the robustness of results and ensure the absence of heterogeneity and horizontal pleiotropy. MR-Steiger was used to assess whether the causal direction was correct to avoid reverse causality. Results This study has shown that Beta-nerve growth factor(Beta-NGF) and Interferon gamma(IFN-gamma) are both involved in the occurrence of LPF and PLI, and they are reducing the risk of occurrence(OR:0.800, 95%CI: 0.650–0.983; OR:0.723, 95%CI:0.568–0.920 and OR:0.812, 95%CI:0.703–0.937; OR:0.828, 95%CI:0.700–0.980). Similarly, Axin-1 and Sulfotransferase 1A1 (SULT-1A1) were causally associated with LPF(OR:0.687, 95%CI:0.501–0.942 and OR:1.178,95%CI:1.010–1.373). Furthermore, Interleukin-4(IL-4), Macrophage inflammatory protein 1a(MIP-1a), and STAM binding protein(STAM-BP) were causally associated with PLI(OR:1.236, 95% CI: 1.058–1.443; OR:1.107, 95% CI: 1.008–1.214 and OR:0.759, 95% CI: 0.617–0.933). The influence of heterogeneity and horizontal pleiotropy were further excluded by sensitivity analysis. Conclusion This study provides new insights into the relationship between circulating inflammatory proteins and LPF and PLI, and may provide new clues for predicting this risk.

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

Cited by 3 publications

References 48 publications

The scaffold protein AXIN1: gene ontology, signal network, and physiological function

The scaffold protein AXIN1: gene ontology, signal network, and physiological function

Craniotubular Dysplasia Ikegawa Type: Further Delineation of the Phenotype

Levels of 91 circulating inflammatory proteins and risk of lumbar spine and pelvic fractures and peripheral ligament injuries: a two-sample mendelian randomization study

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