Researchers show gene variant causes Hajdu-Cheney syndrome, may illuminate bone loss more generally

January 14, 2016
Born to break: Mutation causes fragile bones
A cross-section of the femur of a mouse. The white and purple cells are bone marrow, the pink area is bone, and the arrows show osteoclasts resorbing bone. This mouse has too many osteoclasts; it has a variant of the NOTCH2 gene that causes a disease akin to Hajdu-Cheney syndrome in humans. Credit: Stefano Zanotti/Canalis Lab, UConn Health

Fragile bones are usually an old person's affliction, but sometimes children are born with them. Now, a team of researchers led by UConn professor Ernesto Canalis has shown in mice that a specific gene can cause the disease, called Hajdu-Cheney syndrome. Overabundant bone-absorbing cells may be causing the disorder's characteristic bone loss, and the researchers hope to find a potential treatment.

People born with Hajdu-Cheney syndrome develop misshapen skeletons and bones that quickly start to soften and fracture. Researchers knew Hajdu-Cheney was an inherited disease, but they weren't sure which genetic mutation caused it. They suspected it was in a gene called NOTCH2, which has a specific mutation that appears in people with the syndrome. But Hajdu-Cheney is very rare, and it might just have been a coincidence that families with Hajdu-Cheney also happen to carry an unusual variant of NOTCH2.

To figure out whether the NOTCH2 variant really was responsible, Canalis and his colleagues replicated it in . The result, which will be reported in the 22 January issue of the Journal of Biological Chemistry, was essentially a mouse version of Hajdu-Cheney syndrome.

"Until now, nobody understood why people afflicted with the disease had osteoporosis and fractures," says Canalis, a professor of orthopaedic surgery at UConn Health. His mice seem to provide the answers. They generate a larger pool of osteoclasts, cells that break down and resorb old bone. These cells also mature faster than they do in normal mice. So Hajdu-Cheney mice have far too much bone resorbed by their bodies, and new bone doesn't grow fast enough to replace it. This leads to mice with , very similar to people with the disease.

There are a few symptoms of the disease in humans - such as shortened fingers and oddly shaped skull bones - that the mice don't display. But overall, the mouse model is a very good model of the human disease, Canalis says.

Knowing how the disease works also suggests how it may be treated. If people with Hajdu-Cheney have too many bone-resorbing cells, then it may help to suppress the formation or activity of those cells. And Canalis says scientists know how to do that. His group is currently working on treatments in mice.

Hajdu-Cheney is an incredibly rare disease, with fewer than 100 cases ever described. But there are good scientific reasons to study it. It can illuminate the workings of bone formation and destruction, and give insight into a gene important to both the skeleton and the immune system. It could also possibly tell us about Alagille syndrome, another, much more common genetic associated with NOTCH2. But for Canalis, even if Hajdu-Cheney only affects a few people from a few families, what causes such suffering and how to abate it is worth searching for.

Explore further: Researchers find new way to force stem cells to become bone cells

More information: Ernesto Canalis et al. Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis and Bone Resorption, Journal of Biological Chemistry (2015). DOI: 10.1074/jbc.M115.685453

Related Stories

Researchers find new way to force stem cells to become bone cells

November 16, 2015
Imagine you have a bone fracture or a hip replacement, and you need bone to form, but you heal slowly – a common fact of life for older people. Instead of forming bone, you could form fat. Researchers at the University ...

Inflammation is associated with bone growth

November 30, 2015
Researchers use induced pluripotent stem cells in a mouse model to show that diseased bone growth may be stimulated by a key molecule for inflammation. Inhibition of activin-A was found to repress the bone overgrowth typically ...

Brittle bone disease: Drug research offers hope

March 31, 2015
New research at the University of Michigan offers evidence that a drug being developed to treat osteoporosis may also be useful for treating osteogenesis imperfecta or brittle bone disease, a rare but potentially debilitating ...

Trailblazing trial for brittle-bone disease

October 12, 2015
Foetuses burdened with a crippling form of brittle-bone disease will receive stem-cell treatment early next year in a pioneering trial, the lead researcher told AFP on Monday.

New hope for rare 'stone man' disease, where flesh turns to bone

September 2, 2015
Researchers working with mice believe there's hope for patients with a rare genetic disorder that turns their muscle into bone, in essence immobilizing them in an extra skeleton.

Recommended for you

A math concept from the engineering world points to a way of making massive transcriptome studies more efficient

November 17, 2017
To most people, data compression refers to shrinking existing data—say from a song or picture's raw digital recording—by removing some data, but not so much as to render it unrecognizable (think MP3 or JPEG files). Now, ...

US scientists try first gene editing in the body

November 15, 2017
Scientists for the first time have tried editing a gene inside the body in a bold attempt to permanently change a person's DNA to try to cure a disease.

Genetic mutation in extended Amish family in Indiana protects against aging and increases longevity (Update)

November 15, 2017
The first genetic mutation that appears to protect against multiple aspects of biological aging in humans has been discovered in an extended family of Old Order Amish living in the vicinity of Berne, Indiana, report Northwestern ...

Genetic variant prompts cells to store fat, fueling obesity

November 13, 2017
Obesity is often attributed to a simple equation: People are eating too much and exercising too little. But evidence is growing that at least some of the weight gain that plagues modern humans is predetermined. New research ...

Discovering a protein's role in gene expression

November 10, 2017
Northwestern Medicine scientists have discovered that a protein called BRWD2/PHIP binds to histone lysine 4 (H3K4) methylation—a key molecular event that influences gene expression—and demonstrated that it does so via ...

Twin study finds genetics affects where children look, shaping mental development

November 9, 2017
A new study co-led by Indiana University that tracked the eye movement of twins finds that genetics plays a strong role in how people attend to their environment.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.