Knockout Gene Model Has a Nose for Knockout Breath

Halitosis, or chronic bad breath, afflicts both mice and men, and mice may be used to model human halitosis. But scientists don’t have to put their noses up to mice’s mouths. Just ask the scientists who participated in an international effort to study halitosis at the genetic level.

By studying patients from families afflicted with bad breath, and evaluating mice in which a suspect gene was “knocked out,” or disabled, the scientists identified a potentially frequent inborn error of metabolism that leads to malodor syndrome.

Although most cases of bad breath are associated with bacteria growing in the mouth, up to 3% of people have chronic halitosis of no obvious cause. These people, scientists based at Radboud University in The Netherlands have determined, produce a lot of sulfur-based compounds in their breath, especially methanethiol, which has an unpleasant boiled-cabbage smell. Methanethiol is normally produced during digestion but is broken down in the body.

Some bacteria can break down sulfur compounds. After scrutinizing bacterial genes, the Radboud University scientists identified a gene for a methanethiol oxidase (MTO), an enzyme that resembles a human enzyme, selenium-binding protein 1 (SELENBP1), which has been associated with several cancers.

Like the bacterial MTO, SELENBP1 converts methanethiol to hydrogen peroxide (H₂O₂), formaldehyde, and hydrogen sulfide (H₂S). This activity, one not previously known to exist in humans, is reduced if the gene for SELENBP1 is impaired, for example, by mutations.

Such mutations do in fact occur, the Radboud University scientists and their colleagues at other universities reported. Details appeared December 18 in the journal Nature Genetics, in an article entitled, “Mutations in SELENBP1, Encoding a Novel Human Methanethiol Oxidase, Cause Extraoral Halitosis.”

“We identified mutations in SELENBP1 in five patients with cabbage-like breath odor,” the article’s authors wrote. “The malodor was attributable to high levels of methanethiol and dimethylsulfide, the main odorous compounds in their breath.”

When the scientists looked at their human patients, they found that all had mutations in the SELENBP1 gene that produces this protein and they all had high levels of methanethiol and dimethyl sulfide in their blood. When blood reaches the lungs, these smelly sulfur compounds leave the blood and are exhaled in breath.

Similarly, mice with a genetic knockout of the mouse equivalent of SELENBP1 had low levels of the protein and high levels of methanethiol and other volatile sulfur compounds in their blood.

“Elevated urinary excretion of dimethylsulfoxide was associated with MTO deficiency,” the article’s authors added. “Patient fibroblasts had low SELENBP1 protein levels and were deficient in MTO enzymatic activity; these effects were reversed by lentivirus-mediated expression of wild-type SELENBP1.”

Currently there is no treatment for this form of halitosis, but the genetic studies and a better understanding of sulfur metabolism might lead to treatments in the future. Also, as indicated by study co-author Kent Lloyd, DVM, Ph.D., director of the Mouse Biology Program at the University of California, Davis, it is “important to identify the cause of persistent halitosis, and differentiate that cause from relatively benign causes (e.g., gum disease) and the more morbid causes such as liver cirrhosis.” Although SELENBP1 has been associated with some cancers in human, it is not clear how this association works.

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