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End User Agreement. This publication is distributed under the terms of Article 25fa of the Dutch Copyright Act (Auteurswet) with explicit consent by the author. Dutch law entitles the maker of a short scientific work funded either wholly or partially by Dutch public funds to make that work publicly available for no consideration following a reasonable period of time after the work was first published, provided that clear reference is made to the source of the first publication of the work. This publication is distributed under The Association of Universities in the Netherlands (VSNU) ‘Article 25fa implementation’ pilot project. In this pilot research outputs of researchers employed by Dutch Universities that comply with the legal requirements of Article 25fa of the Dutch Copyright Act are distributed online and free of cost or other barriers in institutional repositories. Research outputs are distributed six months after their first online publication in the original published version and with proper attribution to the source of the original publication. You are permitted to download and use the publication for personal purposes. Please note that you are not allowed to share this article on other platforms, but can link to it. All rights remain with the author(s) and/or copyrights owner(s) of this work. Any use of the publication or parts of it other than authorised under this licence or copyright law is prohibited. Neither Radboud University nor the authors of this publication are liable for any damage resulting from your (re)use of this publication. If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the ma terial inaccessible and/or remove it from the website. Please contact the Library through email: xxxxxxxxx@xxx.xx.xx, or send a letter to: University Library Radboud University Copyright Information Point PO Box 9100 6500 HA Nijmegen You will be contacted as soon as possible. ARTICLES xxxxx://xxx.xxx/10.1038/s41588-017-0006-7 Mutations in SELENBP1, encoding a novel human methanethiol oxidase, cause extraoral halitosis Xxxxx Xxx0, X. Xxxxx Xxxxxxx 2, Xxxxxx ~~Xxxxxxxxxxx0 Artikel~~Xxxxxxxxx0, Xxxxx X. Xxxxxx0,5, Xxx X. Xxxxxxx0, Arjan P. M. xx Xxxxxxx0, Xxxx X. Xxxxx 7, Xxxxx X. Xxxxxx0, Xxxxxxx xxx xxx Xxxxxx0,9, Xxxxxx Xxxxx00, Xxxxx Xxxxxxx00, Marijn Oude Elberink2, Xxxxxxxxx Xxxxxxxx 6, Xxxxxxx X. Xxxxxxxxx 2,9, Xxxx Xxxxxx Xxxx00, X. Xxxxxxx Xxxxxx00, Xxxxxxx Xxxxxxx00, Xxxxx Xxxxxxxxx00, X. Xxxxxx Xxxxxxxx00, Xxxx X. X. Op den Camp 1 and Xxx X. Xxxxxx 2* Selenium-binding protein 1 (SELENBP1) has been associated with several cancers, although its exact role is unknown. We show that SELENBP1 is a methanethiol oxidase (MTO), related to the MTO in methylotrophic bacteria, that converts methanethiol to H2O2, formaldehyde, and H2S, an activity not previously known to exist in humans. We identified mutations in SELENBP1 in five patients with cabbage-like breath odor. The malodor was attributable to high levels of methanethiol and dimethylsulfide, the main odorous compounds 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. Selenbp1-knockout mice showed biochemical characteristics similar to those in humans. Our data reveal a potentially frequent inborn error of metabolism that results from MTO deficiency and leads to a malodor syndrome. T he volatile sulfur-containing compounds hydrogen sulfide (H2S), methanethiol (MT, CH3-SH) and dimethylsulfide (DMS, CH3-S-CH3) have been identified as the main con- tributors to halitosis or bad breath1. The origin of halitosis can be intra- or extraoral2–4. Intraoral halitosis, the most common form, is usually caused by methanethiol and H2S produced by Gram- negative bacteria located on the dorsum of the tongue or in gingi- val and periodontal crevices. Extraoral halitosis has an estimated prevalence of 0.5–3% in the general population2, and its origin is not completely understood. Extraoral bad breath can be caused by conditions affecting the nose, sinuses, tonsils, and esophagus, but in some individuals, the extraoral halitosis is bloodborne3. In blood- borne halitosis, malodorant compounds, most commonly DMS, are carried to the lungs, where they enter the breath3. The DMS con- centrations in oral and nasal breath have been found to be sixfold higher in people with extraoral halitosis than in controls2. 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 complex microbiome and mammalian co-metabolism of volatile sulfur compounds5,6 (Fig. 1). Under phys- iological conditions, methanethiol has three sources in the human body7,8: synthesis from sulfur-containing amino acids by intestinal bacteria; synthesis in intestinal cells through methylation of H2S by thiol S-methyltransferase; and synthesis from methionine through the transamination pathway in human endogenous metabolism. Under pathological conditions, increased levels of DMS can lead to high concentrations of dimethylsulfoxide (DMSO) and dimethyl- sulfone (DMSO2)9. The enzymes involved in these conversions are largely unknown, and gut bacteria are also thought to contribute to the conversion process5,6. Interestingly, people with cancer pro- duce methanethiol and DMS as prominent volatile organic com- pounds10,11. DMS is produced in substantial amounts by lung and liver cancer cell lines10,12 and has been found in lung tumor tissue13. A methanethiol oxidase (MTO) has been purified from the Hyphomicrobium strain VS14,15. This enzyme has 26% similarity at the amino acid level to human SELENBP1, a protein that can bind selenium but whose function is unknown16–18. Low expression of the human gene has been found in several tumors, and a tumor- suppressor function has been suggested for this gene19–21. We hypoth- esized that mutations in SELENBP1 might cause extraoral halitosis. Through studying five patients with extraoral halitosis caused by elevated levels of DMS in the blood, we identified SELENBP1 as the human MTO catalyzing the conversion of methanethiol into formaldehyde, H2S, and hydrogen peroxide (H2O2). Mutations in SELENBP1 cause extraoral halitosis and define a novel inborn error of metabolism. 1Department of Microbiology, IWWR, Faculty of Science, Radboud University, Nijmegen, The Netherlands. 2Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre (RUNMC), Nijmegen, The Netherlands. 3Department of Internal Medicine, RUNMC, Nijmegen, The Netherlands. 4Center for Dentistry and Oral Hygiene, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 5Clinic for Periodontology, Amsterdam, The Netherlands. 6Department of Human Genetics, RUNMC, Nijmegen, The Netherlands. 7Department of Surgery, School of Medicine, and Mouse Biology Program, University of California, Xxxxx, Davis, CA, USA. 8Mouse Biology Program, University of California, Xxxxx, Davis, CA, USA. 9Department of Pediatrics, RUNMC, Nijmegen, The Netherlands. 10Klinik für Kinder und Jugendmedizin, Universitätsklinikum Münster, Münster, Germany. 11Bioanalytics and Biochemistry, Department of Natural Sciences, Bonn-Xxxxx- Xxxx University of Applied Sciences, Rheinbach, Germany. 12Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany. 13School of Life Sciences, University of Warwick, Coventry, UK. 14Centre for Molecular and Biomolecular Informatics, RUNMC, Nijmegen, The Netherlands. 15Metabolic Unit–Pediatric Department, Hospital de Dona Estefânia, CHLC, Lisbon, Portugal. Xxxxx Xxx and X. Xxxxx Xxxxxxx contributed equally to this work. Huub X. X. Op den Camp and Xxx X. Xxxxxx jointly directed this work. *e-mail: xxx.xxxxxx@xxxxxxxxxx.xx NATURE GENETICS | VOL 50 | JANUARY 2018 | 120–129 | xxx.xxxxxx.xxx/xxxxxxxxxxxxxx H2O2 HS CH3 CH2O Bacterial flora Methionine catabolism H3C CH3 MTO H2S Dietary sources H3C CH3 H3C CH3 Dimethyl sulfone (DMSO2) affected individuals in the Dutch family are from a nonconsanguin- eous marriage, and the malodor was their only clinical symptom. The mother of CII-1 and CII-2 had some complaints of halitosis. The parents of the other affected individuals were consanguineous. The affected female in family A had malodor as the only symptom, whereas her brother had a broader spectrum of clinical symptoms with neurological features. The Portuguese affected individual also had neurological sequelae. Breath and body-fluid analyses. For breath and body-fluid analy- ses, we used complementary methods (NMR spectroscopy and gas chromatography) (Table 1). Because of the malodorous body fluid, Hydrogen Formaldehyde Hydrogen NMR spectroscopy was requested for the index patients in the three peroxide sulfide HS CH3 + Methanethiol H2O Water + O2 MTO CH2O + Formaldehyde H2S + Hydrogen sulfide H2O2 DMSO and DMSO2 in the body fluids (Fig. 2b,c). Using gas chromatography with a sulfur-specific detector, we detected high concentrations of an additional sulfur-containing compound, DMS, in the affected individuals (Table 1b). Elevated‌ Fig. 1 | Sulfur metabolism. Diet, bacterial metabolism, and endogenous metabolism contribute to the levels of MT, DMS, DMSO, DMSO2, and catabolites in the body. The main conversion of MT to H2O2, formaldehyde, and H2S by the enzyme MTO is deficient in the patients (indicated by X). Bottom, MTO reaction. All underlined metabolites were confirmed in our assay. Results‌ Patients with extraoral halitosis. We studied five affected individ- uals from three unrelated families with extraoral halitosis causing a cabbage-like breath odor (Fig. 2a). The affected individuals had high levels of DMS in their oral and nasal breath. Known causes, such as intake of DMS-containing food, use of sulfur-containing medication, lower-gastrointestinal problems, and known metabolic defects, such as methionine adenosyltransferase deficiency and tyrosinemia, were excluded. Family A is a German family of Turkish origin and has two affected children (AII-2 and AII-3); family B is Portuguese and has one affected child (BII-2); and family C is Dutch and has two affected children (CII-1 and CII-2). The unifying clini- cal feature across families was the pungent breath malodor. Other clinical signs and symptoms of the affected individuals differed considerably (full description in Supplementary Note). The two blood DMS concentrations have been described in people with extraoral halitosis3,4. Elevated concentrations of DMSO2, an oxida- tion product of DMS, have been observed in the blood of individu- als with methionine adenosyltransferase deficiency9. DMSO2 also occurs in cerebrospinal fluid after intake of DMSO2 as a dietary sup- xxxxxxx00. Additional investigation of breath samples from AII-3 and CII-2 identified elevated levels of a fourth sulfur-containing compound, methanethiol. The methanethiol concentration in the breath of these patients was ten times higher than the highest values in control individuals and unaffected family members. Specialized dental clinics may use portable gas chromatography to detect this specific form of halitosis (breath analysis of CII-2 in Supplementary Fig. 1). We detected elevated methanethiol levels in the urine in some of our patient samples. Because methanethiol is highly volatile and reactive, reproducible quantification of urinary methanethiol was not possible. Patient BII-2 was treated for 5 d with the antibiotic metronida- zole (500 mg oral; three times per day), after which the concentra- tion of DMS in the breath decreased to just above the detection limit. DMS and methanethiol in the urine decreased to 65% after 5 d of metronidazole administration. After cessation of treatment, the DMS levels in the breath and urine returned to pretreatment values. In patient AII-3, a methionine-loading trial was performed. Family A DMSO2 Citric acid Creatinine Creatine DMSO 1 2 4 II 1 3 B I 2 II 1 2 Family Family C 1 2 I II 1 2 3.10 3.00 Creatinine Citric acid Creatine 3.10 3.00 p.p.m. p.p.m.

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