Mice Help Scientists Uncover the Cause of a Rare Disease

The patient had elevated blood levels of the acylcarnitine C5OH, a marker that can indicate biotin (vitamin B7) deficiency. However, treatment with the vitamin did not lead to sustained improvement. Genetic analysis led by Russian Academy of Sciences Corresponding Member Egor Prokhorchuk identified two previously undescribed variants of the SLC5A6 gene, but their link to the disease required confirmation.

The researchers reproduced the same combination of genetic variants in mice and found that the animals developed similar metabolic abnormalities, gained weight more slowly, had reduced physical strength and experienced higher mortality than the control group.

The scientists created a personalized mouse model in which the animals carried the same combination of genetic variants as the patient, Nauchnaya Rossiya reports. The mice developed similar metabolic disturbances, gained weight more slowly, were weaker and had shorter lifespans than the control animals. These findings helped confirm that the identified changes in SLC5A6 were associated with the disease.

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The SLC5A6 gene encodes the sodium-dependent multivitamin transporter (SMVT), a protein that transports vitamins into cells. It delivers several essential nutrients, including biotin and pantothenate (vitamin B5). A malfunctioning transporter can therefore affect not only biotin metabolism but also other physiological processes.

Using the mouse models, the researchers found a possible explanation for why biotin treatment failed to help the patient. In the experiment, biotin supplementation did not extend the lifespan of mice carrying the same combination of genetic variants. In another mouse line carrying a milder SLC5A6 variant, mortality increased following biotin supplementation.

In the model with the same combination of mutations as the patient, C5OH levels decreased, but this was not accompanied by an overall improvement in health. In both mouse lines, changes in biochemical markers indicated impaired fat oxidation.

The authors suggest that when the transporter is not functioning properly, excess biotin may interfere with the uptake of other substances into cells, such as pantothenate. This hypothesis still needs to be tested.

These findings indicate that elevated C5OH levels do not always mean that the body simply lacks biotin. If the usual genetic causes of elevated C5OH have been ruled out, the authors recommend testing the SLC5A6 gene before starting treatment. The personalized mouse model could help researchers investigate the mechanisms underlying this rare disease and identify potential treatment strategies.

“Gene editing in mice has helped solve a mystery that medical geneticists have been facing. Our study has shown that previously unknown mutations in a gene responsible for transporting vitamins into cells can cause a life-threatening and insidious disease. This disorder mimics biotin deficiency, seemingly suggesting that it should be treated with high doses of the vitamin. However, treating the condition with biotin alone is dangerous, as experiments with genetically modified mice have clearly demonstrated. We can see how genetic technologies enable us to understand both how our genes work and how changes to them can cause disease,” says Pyotr Sergiev, director of the A.N. Belozersky Institute of Physico-Chemical Biology at Moscow State University and one of the study's authors.