Scientists have pinpointed a genetic cause of an extremely rare bone-weakening disease seen in young people.
Idiopathic osteoporosis is a bone disease estimated to affect around 0.4 people per 100,000 every year. Like more common forms of osteoporosis, it weakens people's bones, causing them to become brittle. This increases the risk of fractures, even from relatively gentle movements, such as coughing or bending over. Most osteoporosis cases affect people over age 50, particularly postmenopausal women, but idiopathic osteoporosis is different in that it spontaneously arises in young and otherwise healthy individuals.
The exact cause of idiopathic osteoporosis is unknown, but it appears to run in families, with many patients experiencing excessive bone fractures during childhood. This trend suggests that the disease may have a genetic cause — and now, scientists have identified what that cause could be.
Researchers performed a genetic analysis that revealed that mutations in a specific gene can disrupt the function of a protein called MTNR1A, and this may be partly responsible for the development of idiopathic osteoporosis. The scientists published their findings Oct. 16 in the journal Science Translational Medicine. The protein is a receptor on the surface of cells that melatonin, best known as a sleep-promoting supplement, plugs into.
Related: Scientists uncover new hormone in unusual discovery
Melatonin is a hormone that regulates the body's sleep-wake cycle — the daily rhythms that shift the body from sleep to wakefulness and back again. But research shows that melatonin may also have other functions, including the ability to suppress cancer in some contexts, lower blood pressure and control the process of making new bone tissue.
In the new study, scientists sequenced the genomes of 10 people in the same family, several of whom had idiopathic osteoporosis. (The team learned after the study was completed that the family had Ashkenazi Jewish ancestry.)
In addition to the family, the researchers sampled DNA from 75 female patients with the condition who were not related to one another.
This analysis revealed that specific mutations in the gene that codes for MTNR1A — named rs374152717 and rs28383653 — may be tied to the disease, as these mutations were exclusively found in people with the condition.
The team then expanded their investigation to include genomic data from large, publicly available databases. They found that these rare mutations were more commonly found in Ashkenazi Jewish people than in the general population and also tied to idiopathic osteoporosis.
The rs28383653 mutation was particularly prevalent in the female participants with idiopathic osteoporosis, carried by around 4% of people in this population. That's compared to 1.7% in the Ashkenazi population overall, and 0.9% of the general population. The rs374152717 variant, on the other hand, was found in 40% of the family members, 0.9% of the overall Ashkenazi population and 0.04% of the general population. This suggests that people who carry these mutations are at a greater risk of developing idiopathic osteoporosis.
In separate experiments, the researchers used the genome-editing tool CRISPR to insert the rs374152717 mutation into human bone cells, as well as lab mice. The mutation caused the bone cells to make a defunct melatonin receptor, disrupting melatonin signaling. In the mice, the mutation spurred the activity of cells known as osteoblasts, which make bone tissue. This caused the cells to age faster and resulted in a reduction in bone mass.
Taken together, the study findings support the idea that melatonin could potentially be used to treat idiopathic osteoporosis, the team concluded.
"It is possible that by finding means to restore activity of this pathway of melatonin signaling [in these patients], we could prevent further bone loss and fractures or restore bone defects," said Stavroula Kousteni, study co-author and a professor of physiology and cellular biophysics at Columbia University.
However, "these possibilities will need to be tested experimentally," she told Live Science in an email.
Various clinical trials have already shown that melatonin can improve bone density and prevent bone loss, they noted. At this point, the study doesn't point to a way to correct the genetic mutations that may lead to the disease.
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