A University of California San Francisco study looking at links between rare monogenic diseases and levels of vitamin B2 and B3 has uncovered a previously unknown link between levels of vitamin B3 and NAXD disease, a very rare, severe metabolic brain disorder of early childhood.
As reported in Cell, the study shows how specific vitamins could be used as targeted treatments for rare genetic diseases. The researchers also emphasize that the method of widely screening for diseases linked to vitamin B could be applied to many other vitamins and nutrients.
“Among dietary factors, vitamins are uniquely promising as therapies—they are inexpensive, safe, and often bypass regulatory hurdles. Yet, we lack a systematic understanding of which diseases benefit from each vitamin,” write lead author Isha Jain, PhD, a core investigator at the Arc Institute in Palo Alto, and colleagues.
“Specific genetic disorders—such as those affecting vitamin transport or metabolism—remain exquisitely responsive to supplementation, as in riboflavin (B2)-treated Brown Vialetto-Van-Laere syndrome… These examples prompted us to ask: Can we systematically identify all genetic diseases amenable to individual vitamin therapies?”
To try and address this question, Jain and colleagues set out to develop a nutrigenomics framework where they assessed which genetic diseases might be responsive to vitamin supplementation by carrying out a widespread screen.
The investigators switched off genes in human blood‑cancer cells one by one using CRISPR and grew these cells in either low or high levels of vitamin B2 or B3. This let them highlight dozens of inherited diseases that might respond to extra B2 or B3, including several already known to improve with riboflavin supplementation.
The vitamin B2 CRISPR screen highlighted SLC52A2 and FLAD1, genes already known to cause the riboflavin‑responsive disorders Brown‑Vialetto–Van Laere syndrome and a riboflavin‑responsive myopathy.
GPX4, a gene involved in preventing a type of cell death called ferroptosis, was also found to be particularly sensitive to vitamin B2 levels. Model mice with GPX4 disease on a low riboflavin diet had worse symptoms, but high dose vitamin B2 did not significantly improve the disease symptoms in the mice.
The strongest hit in the vitamin B3 screen was for the gene NAXD. In healthy cells, NAXD protein repairs a damaged form of NAD, an important molecule that helps enzymes drive metabolism. Without NAXD, the broken version of NAD builds up and normal NAD is lost. Children born with NAXD mutations develop severe brain disease and often die very young.
Changing dietary levels of vitamin B3 had a dramatic effect in model mice. Removing it from the diet of pregnant mice led to early death of the embryos that did not have functional version of NAXD. In contrast, daily high‑dose injections of a vitamin B3 supplement from birth restored brain NAD and serine, prevented neuropathology, normalized behavior and growth, and extended survival of the same animals more than 40‑fold.
“Beyond NAXD, this framework establishes a blueprint for systematic discovery of nutrient-gene interactions. Our screens nominate multiple additional diseases potentially amenable to B2 or B3 therapy, and the same approach can be extended across all 13 classical vitamins and 50+ micronutrients,” conclude Jain and colleagues.
“Future research will also focus on conducting similar nutritional genetic screens in primary cells to better account for tissue- and cell-type-specific vitamin functions.”
