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A Finnish research group has identified a mutation in the SGMS2 gene — which encodes an enzyme involved in sphingolipid metabolism — in 13 children with childhood-onset osteoporosis or skeletal dysplasia in six unrelated families.

“Our gene [mutation] discovery is important since it involves a group of molecules, namely sphingolipids, that have not been previously implicated in osteoporosis or bone diseases,” senior author Outi Mäkitie, MD, PhD, University of Helsinki, Finland, told Medscape Medical News in an email. 

“It was surprising to us that other mutations in the very same gene can also cause a much more severe skeletal disorder — a skeletal dysplasia — with severe short stature and bone deformities,” she added.

The study, with lead author Minna Pekkinen, PhD, also of the University of Helsinki, was published online February 19 in JCI Insight.

“This [research] will help other patients with a similar bone disease to get a specific diagnosis” and it will help inform genetic counseling in affected families, Mäkitie noted.

Moreover, “in the long run, this discovery may be important for drug development,” to treat not only “patients with this particular genetic form of osteoporosis but even for the more common forms of osteoporosis.”

However, American Society for Bone and Mineral Research (ASBMR) president Bart L. Clarke, MD, from Mayo Clinic College of Medicine, Rochester, Minnesota, cautioned that the researchers “found the gene in six families, all of whom had early onset osteoporosis or skeletal dysplasia.”

Therefore, “this is probably not something that is going to turn out to be present in every patient with osteoporosis that’s diagnosed later in life,” he told Medscape Medical News.

But what is important is that “finding this gene mutation adds to our understanding of the biology of bone gain and loss,” he stressed.

The rare gene mutation, Clarke added, affects an enzyme that produces sphingomyelin, “a lipoprotein that’s been known for many years to contribute to the sheath around nerves and other structures in the body,” but has not previously been connected with bone health.

13 Individuals in Six Families

Osteoporosis is a major clinical and public health concern with significant morbidity, disability, and mortality, but the underlying cause is not well understood, Mäkitie and colleagues write.

Their group, she said, aims to better understand metabolic pathways contributing to bone strength by looking for genetic mutations in individuals with early onset osteoporosis. Previously, they identified a new form of osteoporosis (N Engl J Med. 2013;368:1809-1816).

They recruit children and young adults with rare early onset osteoporosis and perform laboratory tests to exclude participants with nongenetic causes of osteoporosis such as severe vitamin D deficiency or celiac disease.

They then perform whole-exome sequencing and whole-genome sequencing to look for genetic variations that could explain the early onset osteoporosis.

In the current study, the researchers identified heterozygous SGMS2 variants in 13 affected individuals from six unrelated families.

First, they identified SGMS2 gene mutations in three individuals who had childhood-onset osteoporosis from three generations in a Finnish family.

Next, they identified this gene mutation in another individual in another Finnish family, who had a similar disease course with multiple fractures since early childhood.

Then through collaborations with Dutch and American researchers, the group identified four additional families (three white and one Hispanic family) with nine individuals who also had SGMS2 gene mutations.

Four families, including the Finnish patients, had the same nonsense variant in SGMS2 and presented with childhood-onset osteoporosis with or without cranial sclerosis. Two families had a missense variant in SGMS2 and presented with skeletal dysplasia.

Several participants had facial nerve palsy or other neurologic manifestations.

Bone biopsies from three patients, obtained at age 12 to 15 years, showed atypical bone cells and mineralization, and the changes were most apparent in the cortical bone (outer layer of bone).

What Do These Findings Mean?

The results suggest that plasma membrane-bound sphingomyelin metabolism may play a critical role in skeletal homeostasis, the researchers conclude.

Earlier studies have shown that “when the involved cellular pathway is identified in patients with abnormal bone mass, it is possible to develop drugs that specifically target the same pathway to increase bone formation,” Mäkitie explained.

Nevertheless, she conceded, “This naturally requires still a lot of research to really understand how the gene defect leads to bone fragility and what other consequences outside the skeleton the mutations may have.”

“Any drug development requires years of careful research,” Mäkitie summarized, “but based on previous examples I am optimistic that our discovery will turn out to be an important basis for such work.”

Clarke agrees and said, “Potentially, if this protein [does turn out to be] important for bone density and bone loss as people get older, it would be a target that could be treated.” And he noted that the drug might have beneficial effects on nerves too.

“But the question always is, ‘How many people in the population have this mutation?’ It seems to be a rare event, at least where it’s recognized clinically. It may turn out to be significant, but it’s not been tested in huge numbers of patients to find out if they’ve got mutations too.”

Experts suspect that there are probably several hundred genes that are associated with osteoporosis, Clarke continued.

“Right now, we’re still dealing with the range of 20 or so genes that have been reported to cause this. Some are obvious mutations — for example, in the estrogen receptor, changes in collagen synthesis — things that we know would affect bone structure and strength.”

Now this newly discovered mutation in the SGMS2 gene, even though it’s not something that we would directly link [to osteoporosis] turns out to be involved.”

The study was supported by the Academy of Finland, Sigrid Jusélius Foundation, Governmental Subsidy for Clinical Research, Foundation for Pediatric Research, Folkhälsan Research Foundation, Swedish Research Council, Swedish Childhood Cancer Foundation, Novo Nordisk Foundation, German Research Foundation, AUVA (Austrian workers compensation board), WGKK (Viennese sickness insurance funds), Sahlgrenska University Hospital in Gothenburg, IngaBritt and Arne Lundberg Foundation, and Royal 80 Year Fund of King Gustav V. The authors have reported no relevant financial relationships.

JCI Insight. Published online February 19, 2019. Full text

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