Scientists have identified a genetic cause of an extremely rare bone-weakening disease seen in young adults.
Idiopathic osteoporosis is a bone disease that is estimated to affect about 0.4 people per 100,000 each year. Like the most common forms of osteoporosisit 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 cases of osteoporosis affect people over 50 years oldespecially postmenopausal women, but idiopathic osteoporosis is different in that it occurs spontaneously in young and otherwise healthy individuals.
The exact cause of idiopathic osteoporosis is unknown, but it appears to run in the familywith 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 might be.
The 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 partially responsible for the development of idiopathic osteoporosis. The scientists published their findings on October 16 in the journal Science Translational Medicine. The protein is a receptor on the surface of cells that melatonin, better known as a sleep-inducing supplement, attaches to.
Related: Scientists discover a new hormone in an unusual discovery
Melatonin is a hormone that regulates the sleep-wake cycle of the body – the daily rhythms that move the body from sleep to wakefulness and back again. But research shows that melatonin may have other functions, including the ability to suppress cancer in some contexts, low blood pressure AND control the process of creating new bone tissue.
In the new study, scientists sequenced the genomes of 10 people in the same family, some of whom had idiopathic osteoporosis. (The team learned after the study was completed that the family was of Ashkenazi Jewish descent.)
In addition to the family, the researchers took DNA samples from 75 unrelated female patients with the condition.
This analysis revealed that specific mutations in the gene that codes for MTNR1A – called rs374152717 and rs28383653 – may be linked to the disease, as these mutations were found exclusively 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 found more often in Ashkenazi Jews than in the general population and also associated with idiopathic osteoporosis.
The rs28383653 mutation was particularly prevalent in female participants with idiopathic osteoporosis, carried by about 4% of people in this population. This compares to 1.7% in the Ashkenazi population in general and 0.9% of the general population. The rs374152717 variant, on the other hand, was found in 40% of family members, 0.9% of the general 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 introduce the rs374152717 mutation into human bone cells as well as laboratory mice. The mutation caused the bone cells to create a non-functional melatonin receptor, disrupting melatonin signaling. In mice, the mutation boosted the activity of cells known as osteoblastswhich make bone tissue. This caused the cells to age faster and resulted in a reduction in bone mass.
Taken together, the study’s 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 the activity of this melatonin signaling pathway [in these patients]we can prevent further bone loss and fractures or repair bone defects,” he said Stavroula Koustenico-author of the study and professor of cell physiology and 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 does not show a way to correct the genetic mutations that can lead to the disease.
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