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<p>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 <i>BBOX1</i> 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 <i>C. elegans</i> model of <i>BBOX1</i> homolog, <i>gbh-1</i>, and strains harboring patient-derived variants (<i>gbh-1(D72G)</i> for p.Asp59Gly, <i>gbh-1(G283R)</i> for p.Gly263Arg, and <i>gbh-1(G247Vfs6)</i> for p.Gly227Valfs*6), we show very low L-carnitine levels and significantly elevated γ-BB in c.675delA and c.787G&gt;A mutants, and moderately elevated γ-BB in c.176A&gt;G. Furthermore, we observed a lethal embryonic phenotype for the <i>gbh-1</i> 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 <i>C. elegans</i> as a model to study the effects of BBOX1 deficiency.</p>

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Biallelic variants in BBOX1 cause L-Carnitine deficiency and elevated γ-butyrobetaine

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Xiao Li,
  • Mehdi Yeganeh,
  • Graham Sinclair,
  • Jill Mwenifumbo,
  • Karen J. Jacob,
  • Laura Arbour,
  • Anna Lehman,
  • Bojana Rakic,
  • Frédéric M. Vaz,
  • Gabriella Horvath,
  • Maja Tarailo-Graovac,
  • Sylvia Stockler-Ipsiroglu

摘要

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.