Genetically Engineered Mouse Model Mimics Rare Human Bone Disorder

A model for the study of the rare bone disorder Hajdu-Cheney syndrome was developed by genetically engineering a line of mice to express a specific Notch2 mutation.

Notch2 is a member of the notch family of transmembrane proteins that share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells. Mutations within the last coding exon of NOTCH2 have been shown to be the main cause of the Hajdu-Cheney syndrome.

Hajdu-Cheney syndrome—an exceedingly rare disease, with fewer than 100 cases ever described—is characterized by osteoporosis and fractures. Development of this disease is associated with NOTCH2 (neurogenic locus notch homolog protein 2) mutations that result in a truncated stable protein that avoids deactivation by the cell.

To study the relationship between the NOTCH2 mutation and the disease syndrome, investigators at the University of Connecticut (Storrs, USA) created a mouse model that reproduced Hajdu-Cheney syndrome by introducing a mutation in the NOTCH2 locus leading to a change at the amino acid level.

They reported in the December 1, 2015, online edition of the Journal of Biological Chemistry that heterozygous mutants were smaller and had shorter femurs than controls; and at one month of age exhibited cancellous and cortical bone osteopenia (lower than normal bone mineral density). As the mice matured, cancellous bone volume was restored partially in male but not female mice, whereas cortical osteopenia persisted in both sexes. Cancellous bone was found to have an increased number of osteoclasts (bone cells that break down bone tissue) and bone resorption, without a decrease in osteoblast (bone precursor cells) number or bone formation.

"Until now, nobody understood why people afflicted with the disease had osteoporosis and fractures," said first author Dr. Ernesto Canalis, professor of orthopedic surgery at the University of Connecticut. "There are a few symptoms of the disease in humans—such as shortened fingers and oddly shaped skull bones—that the mice do not display. But overall, the mouse model is a very good model of the human disease."

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