Gene of the Month – August: AXIN1
AXIN1 is a core scaffolding protein of the beta-catenin destruction complex. This multiprotein complex facilitates degradation of beta-catenin in cell plasma, resulting in lower levels of the protein, which is required for expression of Wnt target genes. AXIN1 thus acts as a negative regulator of the canonical Wnt signaling pathway, a signaling cascade that has essential functions during embryonic development and also plays an important role in regulating bone homeostasis.
The international research cooperation, led by Professor Uwe Kornak at the Institute of Human Genetics Göttingen, demonstrated that the identified variants result in a loss of the C-terminal DIX domain and lower levels of the AXIN1 protein. Their functional investigations showed an enhanced activity of the canonical Wnt signaling pathway. Treatment of cells with a tankyrase inhibitor attenuated the overactivity. The study results also suggest that AXIN1 coordinates the activity of osteoblasts and osteoclasts.
Terhal P, Venhuizen AJ, Lessel D, Tan WH, 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. AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia. Am J Hum Genet. 2023 Aug 9:S0002-9297(23)00251-3. doi: 10.1016/j.ajhg.2023.07.011. Epub ahead of print.