Homozygous truncating variants in AXIN1 underlie a previously undescribed specific skeletal disorder with a pathological increase in bone tissue and hip dysplasia. The authors of a study published in the American Journal of Human Genetics identified three disease-causing AXIN1 variants in seven patients showing cranial hyperostosis, macrocephaly, hip dysplasia and generalized sclerosis. Analyses in different models involving patient and genome-edited cells provided new insights into AXIN1 function.

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.