Researchers have discovered a completely new way that rickets—a bone disease that weakens children’s bones—can develop. Instead of just lacking vitamin D, some people have a genetic mutation that makes their body produce a broken version of vitamin D that doesn’t work properly. Scientists found that a tiny change in a gene called CYP3A4 causes the body to create an inactive form of vitamin D, leaving bones without the vitamin D they need to grow strong. This discovery opens up new ways to understand and potentially treat this bone disease in people who have this specific genetic mutation.

The Quick Take

  • What they studied: How a genetic mutation in the CYP3A4 gene causes rickets by making the body produce broken vitamin D that doesn’t work
  • Who participated: This was a research discovery study; specific patient numbers were not detailed in the abstract, but the findings apply to people with this particular genetic mutation
  • Key finding: A single genetic change (Ile301Thr) in the CYP3A4 gene causes the body to make an inactive form of vitamin D called 11α,25(OH)2D3, which cannot help bones develop properly
  • What it means for you: If you or a family member has rickets that doesn’t respond to normal vitamin D treatment, genetic testing might reveal this mutation as the cause. This could lead to more targeted treatments in the future, though this discovery is still very new and more research is needed.

The Research Details

This research article describes the discovery of a new genetic cause of rickets. Scientists identified a specific genetic mutation in the CYP3A4 gene that works differently than previously known rickets-causing mutations. Instead of losing function (not working at all), this mutation causes a gain-of-function, meaning the gene works in a new, harmful way. The mutation causes the body to produce an unusual, inactive form of vitamin D that cannot perform its normal job of helping bones absorb calcium and develop properly.

The researchers used advanced molecular and biochemical techniques to understand how this mutant enzyme functions differently from the normal version. They discovered that the enzyme produces 11α,25(OH)2D3, a vitamin D metabolite that the body cannot use effectively. This is a unique finding because most rickets-causing genetic mutations simply break the vitamin D system, whereas this one creates a faulty product instead.

Understanding different genetic causes of rickets is crucial because it helps doctors identify which patients might benefit from which treatments. Some rickets patients don’t respond to standard vitamin D supplements, and this discovery explains why—their bodies might be making broken vitamin D instead of just lacking it. This knowledge could lead to personalized treatment approaches and help researchers develop new therapies specifically targeting this genetic pathway.

This is a research discovery article published in The FEBS Journal, a peer-reviewed scientific journal. The study identifies a novel genetic mechanism, which is significant for advancing our understanding of rickets. However, as a discovery article, it likely focuses on the molecular mechanism rather than large patient studies. Readers should note that this is foundational research that will need follow-up studies in patient populations to fully understand its clinical impact.

What the Results Show

The main discovery is that a specific genetic mutation in the CYP3A4 gene (the change from isoleucine to threonine at position 301) causes a gain-of-function effect. This means the mutated gene doesn’t simply stop working—instead, it works in a new way that harms the body. The mutant enzyme produces an inactive vitamin D metabolite called 11α,25(OH)2D3.

This is fundamentally different from other genetic forms of rickets, where the gene simply loses its ability to function. In those cases, the body can’t activate vitamin D properly. In this new type 3 rickets, the body actually produces a fake, non-functional version of vitamin D. The body’s cells cannot use this inactive metabolite to absorb calcium and build strong bones, leading to rickets symptoms.

This discovery is significant because it reveals an entirely new mechanism by which rickets can develop. The CYP3A4 enzyme is part of the cytochrome P450 family, which are enzymes that modify many different substances in the body. The researchers showed that this particular mutation hijacks the enzyme’s normal function to create a harmful product.

The research highlights how the cytochrome P450 enzyme system can be altered by genetic mutations in unexpected ways. This finding may have implications beyond rickets, as CYP3A4 is involved in metabolizing many medications and other substances in the body. Understanding how mutations can cause gain-of-function effects in these enzymes could help explain other metabolic disorders.

Previously, scientists had identified rickets caused by loss-of-function mutations—where genes simply stop working properly. Type 1 rickets involves problems activating vitamin D, and type 2 rickets involves problems with vitamin D receptors. This new type 3 rickets represents a different category: a gain-of-function mutation that creates a harmful new function. This is a novel discovery that expands our understanding of how genetic mutations can cause rickets and suggests there may be other similar mechanisms yet to be discovered.

The abstract does not specify the number of patients studied or provide detailed clinical data. This appears to be a mechanistic discovery article rather than a large clinical study, so the findings are based on molecular and biochemical analysis rather than extensive patient outcomes. More research is needed to determine how common this mutation is, what symptoms patients with this mutation experience, and how to best treat it. Long-term patient studies will be necessary to develop effective therapies.

The Bottom Line

This research is too new to make specific treatment recommendations. However, it suggests that people with rickets that doesn’t respond to standard vitamin D treatment should consider genetic testing to see if they carry this CYP3A4 mutation. If confirmed, this could lead to personalized treatment approaches. Healthcare providers should stay informed about this discovery as new treatments are developed. Confidence level: Low to moderate, as this is a new discovery requiring further clinical research.

This discovery is most relevant to: (1) Children and adults with rickets that doesn’t respond to normal vitamin D supplements, (2) Families with a history of rickets, (3) Healthcare providers treating rickets patients, and (4) Researchers studying bone metabolism and genetic disorders. People without rickets or those whose rickets responds well to standard treatment are unlikely to be affected by this discovery.

This is foundational research, so practical treatments based on this discovery are likely years away. Scientists will need to conduct further studies to understand the mutation’s effects, develop diagnostic tests, and create targeted treatments. Patients and families should expect a timeline of several years before new therapies become available.

Want to Apply This Research?

  • If you have rickets or suspect you might, track your vitamin D levels (through blood tests ordered by your doctor) and bone health markers over time. Record which treatments you’ve tried and how your symptoms responded. This information will be valuable if you pursue genetic testing.
  • Work with your healthcare provider to get genetic testing if you have rickets that doesn’t respond to standard vitamin D treatment. Keep detailed records of your symptoms, test results, and treatment responses to share with your doctor. Stay informed about new rickets research by discussing it with your healthcare team.
  • Maintain regular check-ups with your healthcare provider to monitor bone health through physical exams and imaging. Track any changes in symptoms like bone pain, weakness, or growth problems. If you’re diagnosed with this CYP3A4 mutation, work with your doctor to monitor how new treatments might become available and whether you’re a candidate for them.

This research describes a newly discovered genetic cause of rickets and is still in the early stages of investigation. The findings are based on molecular research and have not yet been extensively tested in patient populations. If you or a family member has rickets or bone health concerns, consult with a qualified healthcare provider or pediatrician for diagnosis and treatment. Do not attempt to self-diagnose or self-treat based on this information. Genetic testing should only be performed under medical supervision. This article is for educational purposes and should not replace professional medical advice.