Biallelic variants in BBOX1 cause L-Carnitine deficiency and elevated γ-butyrobetaine
Gamma-butyrobetaine hydroxylase (BBOX1) catalyses the last step of carnitine biosynthesis, converting γ-butyrobetaine (γ-BB) into L-carnitine. Here we show, for the first time, that biallelic variants in BBOX1 are associated with decreased levels of L-carnitine and increased plasma levels of γ-BB in three patients from two unrelated families presenting with myopathic, neurodevelopmental, and late-onset psychiatric manifestations. Using a knockout C. elegans model of BBOX1 homolog, gbh-1, and strains harboring patient-derived variants (gbh-1(D72G) for p.Asp59Gly, gbh-1(G283R) for p.Gly263Arg, and gbh-1(G247Vfs6) for p.Gly227Valfs*6), we show very low L-carnitine levels and significantly elevated γ-BB in c.675delA and c.787G>A mutants, and moderately elevated γ-BB in c.176A>G. Furthermore, we observed a lethal embryonic phenotype for the gbh-1 loss-of-function strains, which was rescued upon L-carnitine supplementation. Our study provides novel insights into the clinical and biochemical consequences of BBOX1-related L-carnitine biosynthesis deficiency and establishes C. elegans as a model to study the effects of BBOX1 deficiency.
Authors
- Frédéric M. Vaz (ORCID: https://orcid.org/0000-0002-9048-1041)
- Maja Tarailo‐Graovac (ORCID: https://orcid.org/0000-0002-4472-8584)
- Karen J. Jacob
- Graham B. Sinclair (ORCID: https://orcid.org/0000-0002-3815-2005)
- Bojana Rakić (ORCID: https://orcid.org/0000-0002-3460-6081)
- Jill Mwenifumbo (ORCID: https://orcid.org/0000-0002-1420-1810)
- Sylvia Stöckler‐Ipsiroglu (ORCID: https://orcid.org/0000-0002-6542-423X)
- Laura Arbour (ORCID: https://orcid.org/0000-0002-9589-0880)
- Xiao Li (ORCID: https://orcid.org/0000-0001-5372-2590)
- Gabriella Horváth (ORCID: https://orcid.org/0000-0003-2573-2489)
- Anna Lehman
- Mehdi Yeganeh
Institutions
- University of British Columbia (CA)
- University of Calgary (CA)
- University of Victoria (CA)
- Alberta Children's Hospital (CA)
- Vancouver General Hospital (CA)
- Emma Kinderziekenhuis (NL)
- Children's & Women's Health Centre of British Columbia (CA)
- Amsterdam University Medical Centers (NL)
- BC Children's Hospital (CA)
- University of Amsterdam (NL)
Publication Details
- Journal
- npj Genomic Medicine
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1038/s41525-025-00523-2
- Primary Topic
- Metabolism and Genetic Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Genome Canada
- Children's Hospital Foundation
- BC Children's Hospital
- Genome British Columbia
- Canterbury Medical Research Foundation
- Alberta Children's Hospital Foundation
- Provincial Health Services Authority
- International Microbiome Centre, University of Calgary
- Canadian Institutes of Health Research