Mutations in SELENBP1 encoding methanethiol oxidase, cause extra-oral halitosis

As these GEITP pages have often discussed, the TRAIT (phenotype) being studied in human genetics can be almost anything. And –– if we’re dealing not with a Mendelian trait involving one or a few genes, but rather with a multifactorial trait –– this phenotype will likely reflect contributions from: [a] genetics (variants in DNA sequence); [b] epigenetics (variations due to chromosomal differences other than DNA sequence); and [c] the environment (which can include diet, lifestyle and occupation). Effects that affect the developing embryo and fetus in utero –– can also be considered “the environment”. In the present article [attached], “the environment” includes our microbiome (bacteria that live in the gut and all other orifices of the body).

And the trait chosen to be studied by geneticists can be virtually everything, including HALITOSIS (bad breath). Volatile sulfur-containing compounds –– such as hydrogen sulfide (H2S), methanethiol (CH3-SH) and dimethylsulfide (DMS; CH3-S-CH3) –– have been identified as the key contributors to halitosis. The origin of halitosis can be intra- or extra-oral. Intra-oral halitosis, the most common form, is usually caused by methanethiol and H 2S produced by Gram-negative bacteria located on the tongue or in the gum (gingival) and periodontal crevices. On the other hand, extra-oral halitosis (bad smell outside the mouth) has an estimated prevalence of 0.5–3% in the general population, and its origin is not well understood. Extra-oral bad breath can be caused by conditions affecting the nose, sinuses, tonsils, and esophagus; in some cases, extra-oral halitosis is bloodborne. In bloodborne halitosis, malodorous compounds (most commonly DMS) are carried to the lungs, where they enter the breath. DMS concentrations in oral and nasal breath have been found to be 6-fold higher in people with extra-oral halitosis than in controls.

The cause of elevated DMS levels in these individuals is unknown. DMS is produced from methanethiol through methylation. Both DMS and methanethiol result from the microbiome and mammalian co-metabolism of volatile sulfur compounds. Under physiological conditions, methanethiol has three sources in the human body: [a] synthesis from sulfur-containing amino acids by intestinal bacteria; [b] synthesis in intestinal cells through methylation of H2S by thiol S-methyltransferase; and [c] synthesis from methionine through the trans-amination pathway in human endogenous metabolism. Interestingly, people with cancer produce methanethiol and DMS as prominent volatile organic compounds.

Selenium-binding protein-1 (SELENBP1) has inexplicably been associated with several cancers. Authors [see attached] show that SELENBP1 is a methanethiol oxidase (MTO), related to the MTO in methylotrophic bacteria, that converts methanethiol to hydrogen peroxide (H2O2), formaldehyde, and H2S (this enzymatic activity not previously known to exist in humans). Authors identified DNA variants in the SELENBP1 gene in five patients with “cabbage-like halitosis”. The malodor was attributable to high levels of methanethiol and dimethylsulfide in their breath. Elevated urinary excretion of dimethylsulfoxide was associated with MTO deficiency. 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 in these fibroblasts. Selenbp1-knockout mice showed biochemical characteristics similar to those in humans. These data reveal a potentially frequent inborn error of metabolism that results from MTO deficiency and leads to a “malodor syndrome.”

Nat Genet Jan 2o18; 50: 120–129

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