Congenital rare skeletal disorders are conditions that affect the development and growth of bone and cartilage tissue. In most cases they are genetic in nature. They manifest either as skeletal malformations alone or as characteristic combinations of symptoms that can also involve other tissues. In a collaboration led by Professor Uwe Kornak at the Institute of Human Genetics Göttingen, research teams from Germany, Austria, the Netherlands, Saudi Arabia, and the U.S. have discovered the genetic cause of a previously undescribed specific skeletal disorder. In their study, they identified homozygous variants in the AXIN1 gene in seven patients ranging in age from three months to 15 years old. Radiologically and clinically, these patients presented with a phenotype characterized by generally elevated bone mineral density, excessive skull bone tissue, abnormally large head size (macrocephaly), hip joint malformation, and a developmental delay of variable degree.

The researchers performed additional investigations in different cell models to explore the consequences of the identified variants. This included patient-derived cells as well as cells in which they intentionally introduced the detected AXIN1 variants through genome editing. Their analyses showed that these genetic changes resulted in a smaller amount of functional AXIN1 protein and an enhanced activation of the Wnt signaling pathway.

AXIN1 is a crucial component in the regulation of the beta-catenin-dependent Wnt signaling pathway. This signaling cascade controls fundamental cellular processes during embryonic development and also plays an important role in the balance of bone formation and resorption. AXIN1 has been the subject of extensive research, but no germline variants of this gene have been reported in humans to date. The results of the recent study, published in the American Journal of Human Genetics, suggest that AXIN1 influences the activity of osteoblasts and osteoclasts. These two cell types work together in an intricately coupled manner: osteoblasts form bone tissue while osteoclasts destroy it.

Rare skeletal disorders, their genetic causes and underlying molecular mechanisms and the development of specific gene therapy approaches are a key focus of the Kornak research group at the Institute of Human Genetics Göttingen. New insights gained from their research are directly translated into clinical care at the University Medical Center Göttingen: “In our specialized Center for Rare Skeletal Diseases patients and their families receive individual counselling as well as fast clinical, laboratory, and molecular genetic diagnostics and they have access to specific treatment options. With our research, we aim at advancing the development of new therapeutic approaches and their direct integration into clinical practice”, says Professor Kornak.

AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia
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.
Am J Hum Genet 2023 Aug 9:S0002-9297(23)00251-3. doi: 10.1016/j.ajhg.2023.07.011. Epub ahead of print.