Is an Uncommon Genetic Mutation Linked to Vitamin D-dependent Rickets?

The findings:

Researchers identified a genetic mutation in CYP3A4 that is linked to vitamin D-dependent rickets (VDDR), a childhood disorder associated with impaired growth and skeletal mineralization. Scientists already knew about two other genetic forms of VDDR, but this third kind is caused by a gain-in-function mutation — a random genetic change that confers a new function on a gene — that leads to accelerated inactivation of vitamin D metabolites. This is a new insight into vitamin D metabolism.

Why it matters:

Children with VDDR have weak bones and bone pain that usually affects their ability to walk and grow. They may develop curved (bowed) legs because their bones may not be strong enough to bear weight. Usually, a lack of vitamin D in the diet or not enough exposure to sunlight causes the condition. Genetic forms of VDDR are less common, so it’s important for scientists to better understand the biological pathways underlying the disease, in order to diagnosis patients early in life and begin interventions such as high doses of vitamin D or calcitriol, which is the active form of vitamin D.

Who conducted the study:

An international collaboration led at CHOP included co-first authors Jeffrey Roizen, MD, PhD, a clinician-scientist with CHOP’s Division of Endocrinology and Diabetes, and Dong Li, PhD, a research scientist with the Center for Applied Genomics (CAG) at CHOP. Hakon Hakonarson, MD, PhD, CAG’s director, and Michael Levine, MD, chief of the Division of Endocrinology and Diabetes and medical director of the Center for Bone Health at CHOP also contributed to the study along with researchers from the United Kingdom and Australia.

How they did it:

The study team used whole exome sequence analysis to identify a recurrent new mutation in a single DNA building block (nucleotide) of gene CYP3A4. They determined that the single nucleotide mutation changed the amino acid sequence of the protein that CYP3A4 produces.

Replacement of isoleucine with threonine altered CYP3A4 protein’s activity. Through their experiments, the scientists demonstrated that mutant CYP3A4 protein increased oxidation of vitamin D metabolites with 10-fold greater activity than wild-type CYP3A4. The defect in vitamin D metabolism caused a distinct form of VDDR that occurred in two patients from Australia and the United Kingdom who were not related but remarkably carried the identical gain-of-function mutation in CYP3A4.

Quick thoughts:

“As CYP34A mutations have not previously been linked to rickets, these findings provide new insights into vitamin D metabolism, and demonstrate that the accelerated inactivation of vitamin D metabolites represents a previously undescribed mechanism for vitamin D deficiency,” the study authors wrote.

What’s next:

Although the gain-of-function mutation in CYP3A4 that the study team identified is rare, their findings suggest that physicians consider accelerated vitamin D inactivation as a risk factor for vitamin D deficiency. Physicians also should be aware that changes in CYP3A4 activity could have an effect on the amount of vitamin D necessary to achieve therapeutic benefit.

An additional insight from this study is that naturally occurring variants in the CYP3A4 that are carried in normal people may affect vitamin D metabolism and in part determine how much vitamin D is required by an individual.

“Knowing a person’s CYP3A4 genotype may provide us with information that can guide our recommendations for daily vitamin D intake, bringing us closer to a personalized medicine approach to nutrition,” Dr. Levine said.

Where the study was published:

The article appeared in the Journal of Clinical Investigation.

Where to learn more:

Visit the Division of Endocrinology and Diabetes’ website and the CAG’s website to learn more about the researchers and their current research projects.